Bioorganic & Medicinal Chemistry Letters (v.16, #13)

A versatile access to new macrocyclic oligoheterocycles (MOH) by Adel Nefzi; Rodegar T. Santos (3358-3361).
An efficient and straightforward methodology for the parallel solid-phase synthesis of a variety of new macrocyclic oligoheterocycles is described. Exhaustive reduction of resin-bound cyclic polyamides using borane generates polyamines. Treatment of separated pairs of amines with a variety of bifunctional reagents provides, following cleavage from the solid support, the desired macrocyclic oligoheterocyclic (MOH) compounds in good yields and purities.
Keywords: Solid-phase synthesis; Macrocyclic oligoheterocycles; Polyamines;

Synthesis and SAR of 1,3-disubstituted cyclohexylmethyl urea and amide derivatives as non-peptidic motilin receptor antagonists by Sigmond G. Johnson; Joseph W. Gunnet; John B. Moore; William Miller; Pam Wines; Ralph A. Rivero; Don Combs; Keith T. Demarest (3362-3366).
A novel and potent motilin antagonist series was derived based on an understanding of the key binding elements of a known motilin antagonist.A series of 1,3-disubstituted cyclohexylmethyl urea and amide derivatives were synthesized as motilin receptor antagonists. Starting from known motilin antagonists, 1a and 1b, the cyclopentene scaffold was replaced and the four recognition elements optimized to arrive at a potent novel series.
Keywords: Motilin; Antagonist;

Inhibitors of HCV NS5B polymerase: Synthesis and structure–activity relationships of N-alkyl-4-hydroxyquinolon-3-yl-benzothiadiazine sulfamides by A. Chris Krueger; Darold L. Madigan; Wen W. Jiang; Warren M. Kati; Dachun Liu; Yaya Liu; Clarence J. Maring; Sherie Masse; Keith F. McDaniel; Tim Middleton; Hongmei Mo; Akhteruzzaman Molla; Debra Montgomery; John K. Pratt; Todd W. Rockway; Rong Zhang; Dale J. Kempf (3367-3370).
Substituted N-alkyl-4-hydroxyquinolon-3-yl-benzothiadiazine sulfamides were investigated as inhibitors of genotype 1 HCV polymerase. Structure–activity relationship patterns for this class of compounds are discussed.
Keywords: HCV polymerase antiviral;

Design and synthesis of noncompetitive metabotropic glutamate receptor subtype 5 antagonists by Santosh S. Kulkarni; Barbara Nightingale; Christina M. Dersch; Richard B. Rothman; Amy Hauck Newman (3371-3375).
A series of diaryl amides was designed and synthesized as novel nonethynyl mGluR5 antagonists. The systematic variation of the pharmacophoric groups led to the identification of a lead compound that demonstrated micromolar affinity for the mGluR5. Further optimization resulted in compounds with improved binding affinities and antagonist profiles, in vitro.
Keywords: Metabotropic glutamate receptor subtype 5; mGluR5; Noncompetitive antagonists;

Based on the scaffold of ISO-1, two critical modifications and chiral resolution have significantly improved the potency of the inhibitor up to 20-folds as compared to the parent compound. Compound ( R )-17 inhibits MIF tautomerase with an IC50 of 550 nM.Based on the scaffold of (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1), an inhibitor of the proinflammatory cytokine MIF, two critical modifications and chiral resolution have significantly improved the potency of the inhibition. Compound ( R )-17 is 20-fold more potent than ISO-1 and inhibits MIF tautomerase activity with an IC50 of 550 nM.
Keywords: MIF; ISO-1; Tautomerase activity; Enzyme;

Arylamide derivatives as allosteric inhibitors of the integrin α2β1/type I collagen interaction by Hang Yin; Lars Ole Gerlach; Meredith W. Miller; David T. Moore; Dahui Liu; Gaston Vilaire; Joel S. Bennett; William F. DeGrado (3380-3382).
We herein report a group of allosteric inhibitors of integrin α2β1 based on an arylamide scaffold. Compound 4 showed an IC50 of 4.80 μM in disrupting integrin I-domain/collagen binding in an ELISA. These arylamide compounds are able to block collagen binding to integrin α2β1 on the platelet surface. Further we find that compound 4 recognizes a hydrophobic cleft on the side of the α2 I-domain, suggesting an alternative targeting site for drug development.
Keywords: Integrin; Protein–protein interaction; Platelet adhesion; Allosteric inhibitor;

SAR studies of 2-methoxyestradiol and development of its analogs as probes of anti-tumor mechanisms by Abby Ho; Yang-eon Kim; Hyo-Sung Lee; Kedra Cyrus; Sun-Hee Baek; Kyung-Bo Kim (3383-3387).
The synthesis and use of 2-methoxyestradiol affinity matrix is reported.The major estrogen metabolite 2-methoxyestradiol (2ME) has been shown to target tumor cells without severe side effects and is currently being evaluated in clinical trials for several types of cancer. Despite its promise for use in clinical setting, the mechanism(s) by which 2ME exerts its anti-tumor activity is not clearly defined at this time. Employing organic chemistry tools, we synthesized 2ME analogs with which 2ME affinity column was prepared, enabling us to detect a protein that selectively interacts with 2ME. This 2ME analog will be useful as a probe to identify the biological target(s) of 2ME and study their functions in tumor cells.
Keywords: 2-Methoxyestradiol; Affinity matrix; Biotinylation; Anti-tumor estrogen metabolites;

Efficient synthesis of diacyl-halo-sn-glycerols is reported.Glycidyl esters upon treatment with a mixture of carboxylic acid anhydride (CAA) and trimethylsilyl halide (TMSX) in the presence of tetra-n-butylammonium halide (Bu4NX, X = Cl, Br or I) undergo stereospecific and regioselective opening of the oxirane ring to afford mixed-(or mono)-acid 1,2(2,3)-diacyl-3(1)-halo-sn-glycerols in high yields.
Keywords: Lipid mediator; Glycidol; Diacylglyerols;

Novel linkers and an efficient detection method of bound proteins for small-molecule microarray are reported.Novel isocyanate and diazoketone linkers possessing polyoxypropylenediamine as a spacer for small-molecule microrray are developed. White light interferometry is introduced to detect bound proteins on the glass slides without using chemically modified proteins.
Keywords: Small-molecule microarray; Novel linkers; White light interferometry;

The neuroprotective activity of GPE tripeptide analogues does not correlate with glutamate receptor binding affinity by Sergio A. Alonso De Diego; Marta Gutiérrez-Rodríguez; M. Jesús Pérez de Vega; Rosario González-Muñiz; Rosario Herranz; Mercedes Martín-Martínez; Edurne Cenarruzabeitia; Diana Frechilla; Joaquín Del Río; M. Luisa Jimeno; M. Teresa García-López (3396-3400).
The influence of several modifications on the GPE tripeptide structure upon the binding to GluRs and on their neuroprotective effects has been studied. The results indicated that the prevention of neuronal death showed by GPE and some analogues is not directly related to their affinity at glutamate receptors.
Keywords: Neuroprotection; Glutamate receptors binding; Tripeptides; GPE; Peptidomimetics;

Synthesis and biological evaluation of lisofylline (LSF) analogs as a potential treatment for Type 1 diabetes by Peng Cui; Timothy L. Macdonald; Meng Chen; Jerry L. Nadler (3401-3405).
The LSF analogs were synthesized and evaluated for apoptosis protection, the effect on insulin release and metabolic stability.Lisofylline (LSF, 1-(5-R-hydroxyhexyl)-3,7-dimethylxanthine) is an anti-inflammatory agent that protects β-cells from Th1 cytokine-induced dysfunction and reduces the onset of Type 1 diabetes in non-obese diabetic (NOD) mice. Due to its low potency, poor oral bioavailability, and short half-life, the widespread clinical utility of LSF may be limited. Our goal has been to develop new agents based on the LSF structural motif that resolve the potency and pharmacokinetic liabilities of LSF. In this study, we have generated a focused library of LSF analogs that maintain the side chain (5-R-hydroxyhexyl) constant, while substituting a variety of nitrogen-containing heterocyclic substructures for the xanthine moiety of LSF. This library includes the xanthine-like (5-aza-7-deazaxanthine), as well as non-xanthine-like skeletons. The LSF analogs were evaluated in a pancreatic β-cell line for the effects on apoptosis protection and insulin release. The metabolic stability of selected compounds was also tested.
Keywords: Type 1 diabetes; Lisofylline; LSF; LSF analogs; 5-Aza-7-deazaxanthine;

Arylpiperazines with N-acylated amino acids as 5-HT1A receptor ligands by Paweł Zajdel; Gilles Subra; Andrzej J. Bojarski; Beata Duszyńska; Maciej Pawłowski; Jean Martinez (3406-3410).
A library consisting of 60 arylpiperazines modified with N-acylated amino acids was prepared on BAL linker SynPhase™ Lanterns and evaluated in vitro for 5-HT1A receptor affinity. Biological screening, followed by a simple Fujita–Ban analysis, enabled the description of structure–activity relationships and allowed the selection of some potent, high-affinity ligands for in vivo pharmacological investigations.
Keywords: Long-chain arylpiperazines; Succinimides; Pyroglutamates; Solid-phase synthesis; BAL linker; 5-HT1A receptor ligands; Fujita–Ban analysis;

Antidyslipidemic activity of furano-flavonoids isolated from Indigofera tinctoria by Tadigoppula Narender; Tanvir Khaliq; Anju Puri; Ramesh chander (3411-3414).
Flavonoids appear to play a major role in reducing the risk of cardiovascular diseases by decreasing the blood lipid levels. In continuation of our drug discovery program on antidyslipidemic agents we have isolated three furano-flavones 13 and a rare flavonol glycoside 4 from the aerial parts of Indigofera tinctoria. Our results disclose that the treatment with diastereomeric flavonoid mixture 1 and 2 (80:20) significantly decreased the plasma triglycerides (TG) by 60%, total cholesterol (TC) 19%, glycerol (Gly) 13%, and free fatty acid (FFA) 25% accompanied with increase in high density lipoproteins-cholesterol (HDL-C) by 8% and HDL-C/TC ratio 36% in high fat diet (HFD) fed dyslipidemic hamsters at the dose of 50 mg/kg body weight. The flavonoid 3 has exhibited moderate antidyslipidemic activity.
Keywords: Furano-flavonoids; Antidyslipidemic activity; Hamster model;

Synthesis and SAR of novel histamine H3 receptor antagonists by Cynthia D. Jesudason; Lisa S. Beavers; Jeffrey W. Cramer; Joelle Dill; Don R. Finley; Craig W. Lindsley; F. Craig Stevens; Robert A. Gadski; Samuel W. Oldham; R. Todd Pickard; Christopher S. Siedem; Dana K. Sindelar; Ajay Singh; Brian M. Watson; Philip A. Hipskind (3415-3418).
The synthesis and biological evaluation of novel tetrahydroisoquinoline, tetrahydroquinoline, and tetrahydroazepine antagonists of the human and rat H3 receptors are described.The synthesis and biological evaluation of novel tetrahydroisoquinoline, tetrahydroquinoline, and tetrahydroazepine antagonists of the human and rat H3 receptors are described. The substitution around these rings as well as the nature of the substituent on nitrogen is explored. Several compounds with high affinity and selectivity for the human and rat H3 receptors are reported.
Keywords: Histamine H3 receptor antagonist; Tetrahydroisoquinolines; Tetrahydroquinolines; Tetrahydroazepines;

Thiazolo[5,4-f]quinazolin-9-ones, inhibitors of glycogen synthase kinase-3 by Alexandra Testard; Cédric Logé; Benoît Léger; Jean-Michel Robert; Olivier Lozach; Mélina Blairvacq; Laurent Meijer; Valérie Thiéry; Thierry Besson (3419-3423).
The most selective GSK-3 inhibitors 7ad bind into the ATP-binding site through a key hydrogen bond interaction with Val135 and target the specific hydrophobic backpocket of the enzyme.In an effort to identify new protein kinase inhibitors with increased potency and selectivity, we have developed the microwave-assisted synthesis of thiazolo[5,4-f]quinazolin-9-ones. The effects of eighteen derivatives on CDK1/cyclin B, CDK5/p25, and GSK-3 were investigated. Several turned out to inhibit GSK-3 in the micromolar range. Molecular modeling studies suggest that the most selective GSK-3 inhibitors 7ad bind into the ATP-binding site through a key hydrogen bond interaction with Val135 and target the specific hydrophobic backpocket of the enzyme.
Keywords: Glycogen synthase kinase-3 inhibitors; Quinazolines; Microwave-assisted chemistry; Molecular modeling;

Discovery and SAR of oxindole–pyridine-based protein kinase B/Akt inhibitors for treating cancers by Gui-Dong Zhu; Viraj B. Gandhi; Jianchun Gong; Yan Luo; Xuesong Liu; Yan Shi; Ran Guan; Shayna R. Magnone; Vered Klinghofer; Eric F. Johnson; Jennifer Bouska; Alexander Shoemaker; Anatol Oleksijew; Ken Jarvis; Chang Park; Ron De Jong; Tilman Oltersdorf; Qun Li; Saul H. Rosenberg; Vincent L. Giranda (3424-3429).
We discovered a series of potent and selective oxindole–pyridine-based protein kinase B/Akt inhibitors with an IC50 of 0.17 nM for the most potent compound. Correlation between in vitro selectivity and in vivo efficacy is also discussed.We describe a series of potent and selective oxindole–pyridine-based protein kinase B/Akt inhibitors. The most potent compound 11n in this series demonstrated an IC50 of 0.17 nM against Akt1 and more than 100-fold selectivity over other Akt isozymes. The selectivity against other protein kinases was highly dependent on the C-3 substitutions at the oxindole scaffold, with unsubstituted 9e or 3-furan-2-ylmethylene (11n) more selective and 3-(1H-pyrrol-2-yl)methylene (11f) or 3-(1H-imidazol-2-yl)methylene (11k) less selective. In a mouse xenograft model, 9d, 11f, and 11n inhibited tumor growth but with accompanying toxicity.
Keywords: Akt inhibitor; Protein kinase B; PKB; GSK3; FL5.12-Akt; Anticancer;

Synthesis and evaluation of N-aryl pyrrolidinones as novel anti-HIV-1 agents. Part 1 by Baogen Wu; Kelli Kuhen; Truc Ngoc Nguyen; David Ellis; Beth Anaclerio; Xiaohui He; Kunyong Yang; Donald Karanewsky; Hong Yin; Karen Wolff; Kimberly Bieza; Jeremy Caldwell; Yun He (3430-3433).
N-Aryl pyrrolidinones as novel anti-HIV-1 agents is reported.The synthesis and preliminary structure–activity relationship of a series of pyrrolidinones are described. These pyrrolidinones have been characterized as novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) which are highly potent against wild-type and drug-resistant human immunodeficiency viruses (HIV-1).
Keywords: Antiviral; HIV; NNRTI; Pyrrolidinone;

Design and synthesis of selective keto-1,2,4-oxadiazole-based tryptase inhibitors by James T. Palmer; Robert M. Rydzewski; Rohan V. Mendonca; David Sperandio; Jeffrey R. Spencer; Bernard L. Hirschbein; Julia Lohman; Jeri Beltman; Margaret Nguyen; Liang Liu (3434-3439).
Using a scaleable, directed library approach based on orthogonally protected advanced intermediates, we have prepared a series of potent keto-1,2,4-oxadiazoles designed to explore the P2 binding pocket of human mast cell tryptase, while building in a high degree of selectivity over human trypsin and other serine proteases.
Keywords: Tryptase; Serine protease; Inhibitor; Heterocycle; Ketoheterocycle; Selective; Scaleable process; Pharmacokinetics;

Cell permeation of a Trypanosoma brucei aldolase inhibitor: Evaluation of different enzyme-labile phosphate protecting groups by Laurent Azéma; Christian Lherbet; Cécile Baudoin; Casimir Blonski (3440-3443).
A series of four prodrugs directed against Trypanosoma brucei aldolase bearing various transient enzyme-labile phosphate protecting groups was developed. Herein, we describe the synthesis and evaluation of cell permeation of these prodrugs. The oxymethyl derivative was the most efficient prodrug with a good recovering of the free drug (IC50  = 20 μM) and without any measurable cytotoxicity.
Keywords: Trypanosoma brucei; Aldolase; Phosphate; Inhibitor; Enzyme-labile protecting group; Drug delivery;

Discovery of novel isothiazole inhibitors of the TrkA kinase: Structure–activity relationship, computer modeling, optimization, and identification of highly potent antagonists by Blaise Lippa; Joel Morris; Matthew Corbett; Tricia A. Kwan; Mark C. Noe; Sheri L. Snow; Thomas G. Gant; Melchiorra Mangiaracina; Heather A. Coffey; Barbara Foster; Elisabeth A. Knauth; Matthew D. Wessel (3444-3448).
The design, synthesis, and biological evaluation of potent isothiazole inhibitors of the TrkA kinase is presented.The design, synthesis, and biological evaluation of potent inhibitors of the TrkA kinase is presented. A homology model is created to aid in the enhancement of potency and selectivity of isothiazole inhibitors found during a high-throughput screen. Three different syntheses are utilized to make diverse analogs within this series. Aminoheterocycles are found to be good urea surrogates, whereas bicyclic substituents on the C3 thio group were found to be extremely potent TrkA inhibitors in kinase and cell assays.
Keywords: TrkA; Antagonist; Isothiazole; Homology model; Synthesis;

Privileged structure based ligands for melanocortin-4 receptors—Aliphatic piperazine derivatives by Karin Briner; Iván Collado; Matthew J. Fisher; Cristina García-Paredes; Saba Husain; Steven L. Kuklish; Ana I. Mateo; Thomas P. O’Brien; Paul L. Ornstein; John Zgombick; Óscar de Frutos (3449-3453).
Different substituted cyclic aliphatic piperazines provide useful privileged structures for the construction of ligands with affinity for melanocortin 4 receptors.Aliphatic carbocyclic replacement of the benzyl group of compound 1 yielded compounds with high affinity for the melanocortin-4 receptor (MC4R). Compounds with a cyclohexyl group showed a consistent high affinity, while different polar groups with less basicity were good replacements for the original diethyl amines. Substitution of the polar group found in these privileged structures with an aliphatic moiety produced compounds with high affinity for MC4R.
Keywords: Melanocortin receptors; Privileged structures;

Microwave-enhanced nucleophilic fluorination in the synthesis of fluoropyridyl derivatives of [3,2-c]pyrazolo-corticosteroids, potential glucocorticoid receptor-mediated imaging agents by Michael G.C. Kahn; Emmanuel Konde; Francis Dossou; David C. Labaree; Richard B. Hochberg; Robert M. Hoyte (3454-3458).
Fluoropyridyl derivatives of [3,2-c]pyrazolo-corticosteroids have high affinity for the glucocorticoid receptor (GR) and are highly active glucocorticoids. They are thus considered to be excellent candidates for PET imaging of GR containing tissues when labeled with fluorine-18 (t 1/2  = 110 min). Previously reported syntheses of these fluorinated glucocorticoids were accomplished by conventional thermal nucleophilic halogen exchange reactions with chloropyridyl precursors. These reactions were found to proceed at rates too slow for feasible application to radiosynthesis using [18F]fluoride. We have applied microwave-heating methods to these reactions and found that significant rate enhancements can be realized. Kinetic experiments showed an average relative rate ratio of 3/1 for microwave versus conventional heating and preparative experiments showed an average relative conversion ratio of 4.5/1 during the initial 120 min, a period approximating one half-life of the isotope. The microwave method described was used to prepare previously unreported 2′-(2-fluoro-4-pyridyl)-11β,17,21-trihydroxy-16α-methyl-20-oxo-pregn-4-eno-[3,2-c]-pyrazole, which was evaluated for biological activity.
Keywords: Microwave enhancement; Nucleophilic fluorination; Glucocorticoid imaging agents; Steroid pyrazoles;

Lysine sulfonamides as novel HIV-protease inhibitors: Nε-Acyl aromatic α-amino acids by Brent R. Stranix; Jean-François Lavallée; Guy Sévigny; Jocelyn Yelle; Valérie Perron; Nicholas LeBerre; Dominik Herbart; Jinzi J. Wu (3459-3462).
A series of Nα-isobutyl-Nα-arylsulfonamido-(Nε-acyl aromatic amino acid)lysinol derivatives were prepared and evaluated as inhibitors of HIV protease and viral replication.A series of lysine sulfonamide analogues bearing Nε-acyl aromatic amino acids were synthesized using an efficient synthetic route. Evaluation of these novel protease inhibitors revealed compounds with high potency against wild-type and multiple-protease inhibitor-resistant HIV viruses.
Keywords: HIV protease inhibitor; Lysine; Amino acids; Resistant viral strains;

Novel 1,4-benzodiazepine-2,5-diones as Hdm2 antagonists with improved cellular activity by Kristi Leonard; Juan Jose Marugan; Pierre Raboisson; Raul Calvo; Joan M. Gushue; Holly K. Koblish; Jennifer Lattanze; Shuyuan Zhao; Maxwell D. Cummings; Mark R. Player; Anna C. Maroney; Tianbao Lu (3463-3468).
The disruption of the p53-Hdm2 protein–protein interaction induces cell growth arrest and apoptosis. We have identified the 1,4-benzodiazepine-2,5-dione scaffold as a suitable template for inhibiting this interaction by binding to the Hdm2 protein. Several compounds have been made with improved potency, solubility, and cell-based activities.
Keywords: Hdm2; p53; Benzodiazepinedione;

DNA sequence recognition by an imidazole-containing isopropyl-substituted thiazole polyamide (thiazotropsin B) by Andrew J. Hampshire; Hannah Khairallah; Abedawn I. Khalaf; Abdolrasoul H. Ebrahimabadi; Roger D. Waigh; Colin J. Suckling; Tom Brown; Keith R. Fox (3469-3474).
Thiazotropsin B binds to the sequence (A/T)CGCG(T/A).We have used DNA footprinting and fluorescence melting experiments to study the sequence specific binding of an imidazole-containing isopropyl-substituted thiazole polyamide (thiazotropsin B) to DNA. While the parent compound (thiazotropsin A) binds to the hexanucleotide sequence ACTAGT, changing one of the N-methylpyrrole groups to N-methylimidazole changes the preferred binding sequence to (A/T)CGCG(T/A). Experiments with DNA fragments that contain variants of this sequence suggest that the ligand can also bind, with lower affinity, to sequences which differ from this by 1 bp in any position.
Keywords: DNA recognition; Footprinting; Minor groove ligand;

Synthesis and structure–activity studies of antibacterial oxazolidinones containing dihydrothiopyran or dihydrothiazine C-rings by Adam R. Renslo; Gary W. Luehr; Stuart Lam; Neil E. Westlund; Marcela Gómez; Corrine J. Hackbarth; Dinesh V. Patel; Mikhail F. Gordeev (3475-3478).
A new series of oxazolidinone analogs bearing unsaturated sulfur-containing C-rings is described. New synthetic approaches to the dihydrothiazine ring system are also disclosed.A new series of antimicrobial oxazolidinones bearing unsaturated heterocyclic C-rings is described. Dihydrothiopyran derivatives were prepared from the saturated tetrahydrothiopyran sulfoxides via a Pummerer-rearrangement/elimination sequence. Two new synthetic approaches to the dihydrothiazine ring system were explored, the first involving a novel trifluoroacetylative-detrifluoroacetylative Pummerer-type reaction sequence and the second involving direct dehydrogenation of tetrahydrothiopyran S,S-dioxide intermediates. Final analogs such as 4 and 13 represent oxidized congeners of recent pre-clinical and clinical oxazolidinones.
Keywords: Antibacterials; Oxazolidinones; Dihydrothiazine; Dihydrothiopyran;

Phosphonic acid-containing analogues of mycophenolic acid as inhibitors of IMPDH by William J. Watkins; James M. Chen; Aesop Cho; Lee Chong; Nicole Collins; Maria Fardis; Wei Huang; Magdeleine Hung; Thorsten Kirschberg; William A. Lee; Xiaohong Liu; William Thomas; Jie Xu; Ameneh Zeynalzadegan; Jennifer Zhang (3479-3483).
The design, synthesis, and IMPDH inhibitory activity of a series of phosphonic acid-containing analogues of mycophenolic acid are described.The design, synthesis, and IMPDH inhibitory activity of a series of phosphonic acid-containing analogues of mycophenolic acid are described.
Keywords: IMPDH; Immunosuppression; Transplant; Mycophenolic acid; Phosphonic acid; Enzyme inhibitor;

Heteroaryl substituted bis-trifluoromethyl carbinols as malonyl-CoA decarboxylase inhibitors by Jie-Fei Cheng; Chi Ching Mak; Yujin Huang; Richard Penuliar; Masahiro Nishimoto; Lin Zhang; Mi Chen; David Wallace; Thomas Arrhenius; Donald Chu; Guang Yang; Miguel Barbosa; Rick Barr; Jason R.B. Dyck; Gary D. Lopaschuk; Alex M. Nadzan (3484-3488).
A series of heteroaryl-substituted bis-trifluoromethyl carbinols 3 were prepared and evaluated as malonyl-CoA decarboxylase inhibitors. Several thiazole derivatives showed potent in vitro inhibitory activities and caused a 5-fold stimulation of glucose oxidation rates in isolated working rat hearts.A series of heteroaryl-substituted bis-trifluoromethyl carbinols were prepared and evaluated as malonyl-CoA decarboxylase (MCD) inhibitors. Some thiazole-based derivatives showed potent in vitro MCD inhibitory activities and significantly increased glucose oxidation rates in isolated working rat hearts.
Keywords: Malonyl-CoA; Acetyl-CoA; Malonyl-CoA decarboxylase; MCD; Fatty acid oxidation; Glucose oxidation;

The discovery of tetrahydrofluorenones as a new class of estrogen receptor β-subtype selective ligands by R.R. Wilkening; R.W. Ratcliffe; E.C. Tynebor; K.J. Wildonger; A.K. Fried; M.L. Hammond; R.T. Mosley; P.M.D. Fitzgerald; N. Sharma; B.M. McKeever; S. Nilsson; M. Carlquist; A. Thorsell; L. Locco; R. Katz; K. Frisch; E.T. Birzin; H.A. Wilkinson; S. Mitra; S. Cai; E.C. Hayes; J.M. Schaeffer; S.P. Rohrer (3489-3494).
Synthesis and derivatization of a series of substituted tetrahydrofluorenone analogs giving potent, ERβ subtype-selective ligands are described.Synthesis and derivatization of a series of substituted tetrahydrofluorenone analogs giving potent, ERβ subtype selective ligands are described. Several analogs possessing ERβ binding affinities comparable to 17β-estradiol but with greater than 75-fold selectivity over ERα are reported.
Keywords: Estrogen receptor ligands; Tetrahydrofluorenone;

Electron-donating substituents decrease the psychotomimetic activity trough a specific effect relating to the diminution of the conjugative electron release from the 5-methoxy group to the phenyl ring.Electron-withdrawing substituents at position 4 of 2,5-dimethoxy-substituted amphetamines increase, whereas electron-donating substituents decrease the psychotomimetic activity. The origin of this clearly localized effect is discussed. The uses of modified Hammett substituent scales (σ and σ +), and especially the good σ + correlation, strongly suggest that electron-donating substituents decrease the biological activity through a specific effect relating to the extent of the conjugative electron release from the 5-methoxy group to the phenyl ring.
Keywords: Psychotomimetic activity; Substituent effects; Amphetamines; Resonance effects;

Synthesis and antibacterial activity of new fluoroquinolones containing a substituted N-(phenethyl)piperazine moiety by Alireza Foroumadi; Shahram Ghodsi; Saeed Emami; Somayyeh Najjari; Nasrin Samadi; Mohammad Ali Faramarzi; Leila Beikmohammadi; Farshad H. Shirazi; Abbas Shafiee (3499-3503).
Novel N-substituted piperazinyl quinolone derivatives, which bear a 2-aryl-2-methoxyiminoethyl substituent and some related residues in the 4-position of the piperazine ring, have been synthesized and evaluated for antimicrobial activity. Some ciprofloxacin derivatives showed in vitro Gram-positive and Gram-negative activity superior to that of reference quinolones. N-(Phenethyl)piperazinyl quinolone derivatives that bear a methoxyimino-substituent have been synthesized and evaluated for antimicrobial activity against Gram-positive and Gram-negative microorganisms. In addition, to define structure–activity relationships, ciprofloxacin derivatives containing 2-oxo-2-phenylethyl or 2-hydroxyimino-2-phenylethyl moieties at N-4 position of piperazine ring were prepared and tested. Ciprofloxacin derivatives, containing a N-(chloro-substituted phenethyl) residue, showed in vitro Gram-positive and Gram-negative activity generally comparable or superior to that of reference quinolones.
Keywords: Piperazinyl quinolones; Ciprofloxacin derivatives; Antimicrobial activity; Methoxyimino-substituent;

Identification and characterization of 4-aryl-3,4-dihydropyrimidin-2(1H)-ones as inhibitors of the fatty acid transporter FATP4 by Christopher Blackburn; Bing Guan; James Brown; Courtney Cullis; Stephen M. Condon; Tracy J. Jenkins; Stephane Peluso; Yingchun Ye; Ruth E. Gimeno; Sandhya Punreddy; Ying Sun; Hui Wu; Brian Hubbard; Virendar Kaushik; Peter Tummino; Praveen Sanchetti; Dong Yu Sun; Tom Daniels; Effie Tozzo; Suresh K. Balani; Prakash Raman (3504-3509).
Several potent, cell permeable 4-aryl-dihydropyrimidinones have been identified as inhibitors of FATP4. Lipophilic ester substituents at the 5-position and substitution at the para-position (optimal groups being –NO2 and CF3) of the 4-aryl group led to active compounds. In two cases racemates were resolved and the S enantiomers shown to have higher potencies.Several potent, cell permeable 4-aryl-dihydropyrimidinones have been identified as inhibitors of FATP4. Lipophilic ester substituents at the 5-position and substitution at the para-position (optimal groups being –NO2 and CF3) of the 4-aryl group led to active compounds. In two cases racemates were resolved and the S enantiomers shown to have higher potencies.
Keywords: FATP4 inhibitor; Fatty acid; Biginelli condensation;

Development of N-2,4-pyrimidine-N-phenyl-N′-phenyl ureas as inhibitors of tumor necrosis factor alpha (TNF-α) synthesis. Part 1 by Todd A. Brugel; Jennifer A. Maier; Michael P. Clark; Mark Sabat; Adam Golebiowski; Roger G. Bookland; Matthew J. Laufersweiler; Steven K. Laughlin; John C. VanRens; Biswanath De; Lily C. Hsieh; Marlene J. Mekel; Michael J. Janusz (3510-3513).
A new class of tumor necrosis factor alpha (TNF-α) synthesis inhibitors based on an N-2,4-pyrimidine-N-phenyl-N′-phenyl urea scaffold is described.A new class of tumor necrosis factor alpha (TNF-α) synthesis inhibitors based on an N-2,4-pyrimidine-N-phenyl-N′-phenyl urea scaffold is described. Many of these compounds showed low-nanomolar activity against lipopolysaccharide stimulated TNF-α production. X-ray co-crystallization studies with mutated p38α showed that these trisubstituted ureas interact with the ATP-binding pocket in a pseudo-bicyclic conformation brought about by the presence of an intramolecular hydrogen bonding interaction.
Keywords: Cytokine synthesis inhibitors; p38α kinase; Urea;

Development of N-2,4-pyrimidine-N-phenyl-N′-alkyl ureas as orally active inhibitors of tumor necrosis factor alpha (TNF-α) synthesis. Part 2 by Jennifer A. Maier; Todd A. Brugel; Michael P. Clark; Mark Sabat; Adam Golebiowski; Roger G. Bookland; Matthew J. Laufersweiler; Steven K. Laughlin; John C. VanRens; Biswanath De; Lily C. Hsieh; Kimberly K. Brown; Karen Juergens; Richard L. Walter; Michael J. Janusz (3514-3518).
A new class of tumor necrosis factor alpha (TNF-α) synthesis inhibitors based on an N-2,4-pyrimidine-N-phenyl-N′-alkyl urea scaffold is described.A new class of tumor necrosis factor alpha (TNF-α) synthesis inhibitors based on a N-2,4-pyrimidine-N-phenyl-N′-alkyl urea scaffold is described. Many of these compounds showed low-nanomolar activity against lipopolysaccharide stimulated TNF-α production. Two analogs were tested in an in vivo rat iodoacetate model of osteoarthritis and shown to be orally efficacious. X-ray co-crystallization studies with mutated p38α showed that these trisubstituted ureas interact with the ATP-binding pocket in a pseudo-bicyclic conformation brought about by the presence of an intramolecular hydrogen bonding interaction.
Keywords: Cytokine synthesis inhibitors; p38α kinase; Urea;

The heptapeptide IQTTWSR (IQ), recently reported as inhibitor of the β-amyloid (Aβ) binding to nicotinic acetylcholine receptors (nAChrs), was docked to the homology model of the α7 nicotinic acetylcholine receptor. The most representative models were further subjected to molecular dynamics simulations. The data obtained here suggest that Aβ needs highly specific structural motifs to bind to the α7nAChR. These structural motifs are located principally in the upper and lower surroundings of loop C, including loop F and sheets β1, β2, β6, β9, and β10 of the receptor. Overall, these results suggest that IQ can be mimicked by more bioavailable, stable compounds that would be helpful for the understanding of the Aβ binding site and its dynamics, and for the design of novel agents to be used as an effective alternative against Alzheimer’s disease.
Keywords: Alzheimer’s disease; α7 Nicotinic acetylcholine receptor; β-Amyloid peptide; Docking; Molecular dynamics simulations; Drug design;

3-(4-Piperidinyl)indoles and 3-(4-piperidinyl)pyrrolo-[2,3-b]pyridines as ligands for the ORL-1 receptor by Gilles C. Bignan; Kathleen Battista; Peter J. Connolly; Michael J. Orsini; Jingchun Liu; Steven A. Middleton; Allen B. Reitz (3524-3528).
The synthesis and biological evaluation of a series of 3-(4-piperidinyl)indoles and 3-(4-piperidinyl)pyrrolo[2,3-b]pyridines afforded compounds with high ORL-1 affinity.A novel series of indoles and 1H-pyrrolo[2,3-b]pyridines having a piperidine ring at the 3-position were synthesized and found to bind with high affinity to the ORL-1 receptor. Structure–activity relationships at the piperidine nitrogen were investigated in each series. Substitution on the phenyl ring and nitrogen atom of the indole and 1H-pyrrolo[2,3-b]pyridine cores generated several selective high-affinity ligands that were agonists of the ORL-1 receptor.
Keywords: ORL-1; Nociceptin; Opioid receptor-like (ORL); Orphanin FQ (OFQ); N/OFQ peptide (NOP); Agonist; Indole; Piperidine; Pyridine; Anxiety; Stress; Learning; Memory;

Synthesis of Hsp90 dimerization modulators by Gabriela Chiosis; Julia Aguirre; Christopher V. Nicchitta (3529-3532).
The synthesis and evaluation of several Hsp90 chemical modulators is reported.The synthesis and evaluation of several chemical modulators of heat shock protein 90 (Hsp90) dimerization is presented. These agents may represent useful tools to study the importance of N-terminal dimerization and also to determine subunit interface(s) in Hsp90.
Keywords: Hsp90; Chemical modulator of dimerization; Geldanamycin;

Modulators of the human CCR5 receptor. Part 3: SAR of substituted 1-[3-(4-methanesulfonylphenyl)-3-phenylpropyl]-piperidinyl phenylacetamides by John G. Cumming; Simon J. Brown; Anne E. Cooper; Alan W. Faull; Anthony P. Flynn; Ken Grime; John Oldfield; John S. Shaw; Emma Shepherd; Howard Tucker; David Whittaker (3533-3536).
SAR and PK studies led to the identification of compound 9g as a highly potent and selective ligand for the human CCR5 chemokine receptor with good oral pharmacokinetic properties.SAR and PK studies led to the identification of N-(1-{(3R)-3-(3,5-difluorophenyl)-3-[4-methanesulfonylphenyl] propyl}piperidin-4-yl)-N-ethyl-2-[4-methanesulfonylphenyl]acetamide as a highly potent and selective ligand for the human CCR5 chemokine receptor with good oral pharmacokinetic properties.
Keywords: CCR5 modulator; CCR5 antagonist; Chemokine receptor; CCR5;

Electron-rich 6-[(dimethylamino)methylene]amino uracil 1 undergoes [4+2] cycloaddition reactions with various in situ generated glyoxylate imine and imine oxides to provide novel pyrimido[4,5-d]pyrimidine derivatives of biological significance, after elimination of 1,3-dimethylamine from the (1:1) cycloadducts and oxidative aromatisation.Electron rich 6-[(dimethylamino)methylene]amino uracil 1, undergoes [4+2] cycloaddition reactions with various in situ generated glyoxylate imine and imine oxides 6 to provide novel pyrimido[4,5-d]pyrimidine derivatives of biological significance, after elimination of dimethylamine from the (1:1) cycloadducts and oxidative aromatisation. This procedure provides a convenient method for the direct synthesis of pyrimido[4,5-d]pyrimidines in excellent yields when carried out in the solid state and under microwave irradiations.
Keywords: Pyrimido[4,5-d]pyrimidines; Microwave irradiations; Solvent-free conditions; Glyoxylate imines; Diaryl nitrones;

Synthesis and biological investigation of S-aryl-S-DABO derivatives as HIV-1 inhibitors by Claudia Mugnaini; Fabrizio Manetti; José A. Esté; Imma Clotet-Codina; Giovanni Maga; Reynel Cancio; Maurizio Botta; Federico Corelli (3541-3544).
S-Aryl-S-DABO derivatives, a novel subclass of S-DABO anti-HIV-1 agents, were synthesized via Ullmann type reaction starting from the corresponding 2-thiouracils by the aid of microwave irradiation. The results of their evaluation as inhibitors of RT are reported together with their antiviral activity in cellular assays.
Keywords: HIV-1; RT inhibitors; S-DABO derivatives; Pyrimidinones; Microwave-assisted synthesis;

Synthesis and antibacterial activity of nocathiacin I analogues by B. Narasimhulu Naidu; Margaret E. Sorenson; John D. Matiskella; Wenying Li; Justin B. Sausker; Yunhui Zhang; Timothy P. Connolly; Kin S. Lam; Joanne J. Bronson; Michael J. Pucci; Hyekyung Yang; Yasutsugu Ueda (3545-3549).
The synthesis and antibacterial activity of nocathiacin I analogues is described.Stereoselective reduction of dehydroalanine double bond in nocathiacin I afforded the primary amide 2. Enzymatic hydrolysis of the amide 2 provided the carboxylic acid 3, which upon coupling with a variety of amines furnished amides 432. Some of these semi-synthetic derivatives have retained very good antibacterial activity and have improved aqueous solubility.
Keywords: Nocathiacin I; Antibacterial activity;

2,3,7-Trisubstituted pyrazolo[1,5-d][1,2,4]triazines: Functionally selective GABAA α3-subtype agonists by Robert W. Carling; Michael G.N. Russell; Kevin W. Moore; Andrew Mitchinson; Alexander Guiblin; Alison Smith; Keith A. Wafford; George Marshall; John R. Atack; Leslie J. Street (3550-3554).
Novel synthetic routes have been devised for the preparation of previously inaccessible 2,3,7-trisubstituted pyrazolo[1,5-d][1,2,4]triazines 2. These compounds are high affinity, functionally selective ligands for GABAA α3-containing benzodiazepine receptors.Novel synthetic routes have been devised for the preparation of previously inaccessible 2,3,7-trisubstituted pyrazolo[1,5-d][1,2,4]triazines 2. These compounds are high affinity ligands for the GABAA benzodiazepine binding site and some analogues show functional selectivity for agonism at α3-containing receptors over α1-containing receptors with the lead compound being 32.
Keywords: GABAA-Benzodiazepine-modulatory-site; Subtype-selective-agonists; Pyrazolo[1,5-d][1,2,4]triazines;

Function of the alkyl side chains of Δlac-acetogenins in the inhibitory effect on mitochondrial complex I (NADH-ubiquinone oxidoreductase) by Naoya Ichimaru; Masato Abe; Masatoshi Murai; Mai Senoh; Takaaki Nishioka; Hideto Miyoshi (3555-3558).
We synthesized a series of Δlac-acetogenins in which the two alkyl side chains were systematically modified, and examined their inhibitory effect on bovine heart mitochondrial complex I (NADH-ubiquinone oxidoreductase). The results revealed that the physicochemical properties of the side chains, such as the balance of hydrophobicity and the width (or bulkiness) of the chains, are important structural factors for a potent inhibitory effect of amphiphilic Δlac-acetogenins. This is probably because such properties decide the precise location of the hydrophilic bis-THF ring moiety in the enzyme embedded in the inner mitochondrial membrane.
Keywords: Complex I; Respiratory inhibitor; Acetogenin; Structure–activity relationship;

Carboxylate bioisosteres of pregabalin by Jacob B. Schwarz; Norman L. Colbry; Zhijian Zhu; Brian Nichelson; Nancy S. Barta; Kristin Lin; Raymond A. Hudack; Sian E. Gibbons; Paul Galatsis; Russell J. DeOrazio; David D. Manning; Mark G. Vartanian; Jack J. Kinsora; Susan M. Lotarski; Zheng Li; Melvin R. Dickerson; Ayman El-Kattan; Andrew J. Thorpe; Sean D. Donevan; Charles P. Taylor; David J. Wustrow (3559-3563).
Truncation and acid replacement with tetrazole furnished a compound with a similar pattern of activity to pregabalin.Several β-amino tetrazole analogs of gabapentin 1 and pregabalin 2 were prepared by one of two convergent, highly efficient routes, and their affinity for the α2–δ protein examined. Two select compounds with potent affinity for α2–δ, 8a and 16a, were subsequently tested in vivo in an audiogenic seizure model and found to elicit protective effects.
Keywords: Gabapentin; Pregabalin; α2–δ Subunit; Tetrazole;

2-Aryl(pyrrolidin-4-yl)acetic acids are potent agonists of sphingosine-1-phosphate (S1P) receptors by Lin Yan; Richard Budhu; Pei Huo; Christopher L. Lynch; Jeffrey J. Hale; Sander G. Mills; Richard Hajdu; Carol A. Keohane; Mark J. Rosenbach; James A. Milligan; Gan-Ju Shei; Gary Chrebet; James Bergstrom; Deborah Card; Suzanne M. Mandala (3564-3568).
A series of 2-aryl(pyrrolidine-4-yl)acetic acids (e.g., 22g) were synthesized and evaluated as S1P receptor agonists and were found to lower peripheral lymphocyte counts in mice and to have good overall pharmacokinetic properties in rat.A series of 2-aryl(pyrrolidin-4-yl)acetic acids were synthesized and their biological activities were evaluated as agonists of S1P receptors. These analogs were able to induce lowering of lymphocyte counts in the peripheral blood of mice and were found to have good overall pharmacokinetic properties in rat.
Keywords: Immunosuppressants; S1P agonists; (Pyrrolidin-4-yl)acetic acids; Peripheral lymphocyte lowering;

Design, synthesis, and biological evaluation of indole derivatives as novel nociceptin/orphanin FQ (N/OFQ) receptor antagonists by Yuichi Sugimoto; Atsushi Shimizu; Tetsuya Kato; Atsushi Satoh; Satoshi Ozaki; Hisashi Ohta; Osamu Okamoto (3569-3573).
A novel series of 2-(1,2,4-oxadiazol-5-yl)-1H-indole derivatives as nociceptin/orphanin FQ (N/OFQ) receptor antagonists was discovered.A novel series of 2-(1,2,4-oxadiazol-5-yl)-1H-indole derivatives as nociceptin/orphanin FQ (N/OFQ) receptor antagonists was discovered. Systematic modification of our original lead by changing the pendant functional groups, linker, heterocyclic core, and basic side chain revealed the structure–activity requirements for this novel template and resulted in the identification of more potent analog with improved potency as compared to the parent compound.
Keywords: Nociceptin; Orphanin FQ; ORL-1 receptor; Antagonist; Indole;

Development of sulfonamide compounds as potent methionine aminopeptidase type II inhibitors with antiproliferative properties by Megumi Kawai; Nwe Y. BaMaung; Steve D. Fidanze; Scott A. Erickson; Jason S. Tedrow; William J. Sanders; Anil Vasudevan; Chang Park; Charles Hutchins; Kenneth M. Comess; Douglas Kalvin; Jieyi Wang; Qian Zhang; Pingping Lou; Lora Tucker-Garcia; Jennifer Bouska; Randy L. Bell; Richard Lesniewski; Jack Henkin; George S. Sheppard (3574-3577).
Synthesis and biological activity of novel methionine aminopeptidase type -2 inhibitors having a sulfonamide bond are reported.We have screened molecules for inhibition of MetAP2 as a novel approach toward antiangiogenesis and anticancer therapy using affinity selection/mass spectrometry (ASMS) employing MetAP2 loaded with Mn2+ as the active site metal. After a series of anthranilic acid sulfonamides with micromolar affinities was identified, chemistry efforts were initiated. The micromolar hits were quickly improved to potent nanomolar inhibitors by chemical modifications guided by insights from X-ray crystallography.
Keywords: MetAP2; Sulfonamide; Antiproliferative;

New potential inhibitors of cyclin-dependent kinase 4: Design and synthesis of pyrido[2,3-d]pyrimidine derivatives under microwave irradiation by Shujiang Tu; Jinpeng Zhang; Xiaotong Zhu; Jianing Xu; Yan Zhang; Qian Wang; Runhong Jia; Bo Jiang; Junyong Zhang (3578-3581).
The synthesis of pyrido[2,3-d]pyrimidine derivatives as new potential inhibitors of Cdk4 is reported.A simple and efficient synthesis of 2-amino pyrido[2,3-d]pyrimidine derivatives was accomplished via a three-component reaction under microwave irradiation without catalyst. This method had many dramatic advantages such as the short reaction time, high yield, and broad substrate scope, as well as convenient operation. We provide new series of potential biologically active compounds as inhibitors of Cdk4.
Keywords: Pyrido[2,3-d]pyrimidine; Microwave irradiation; Cdk4;

The ortho hydroxy-amino group: Another choice for synthesizing novel antioxidants by Weijun Chen; Ping Guo; Jirong Song; Wei Cao; Jiang Bian (3582-3585).
The ortho hydroxy-amino group can be used as another choice for synthesizing novel antioxidants?Four ortho hydroxy-amino derivatives have been designed based on the structures of flavonoids to explore the effect of the ortho hydroxy-amino group on the antioxidant properties of molecules, and their bond dissociation enthalpies (BDE), ionization potentials (IP), the highest occupied molecular orbitals (HOMO), and spin densities have been calculated. The results reveal that the ortho hydroxy-amino group plays an important role in promoting the antioxidant properties of molecules because of its lowering effect on BDE, IP, and spin density. The derivatives with ortho hydroxy-amino group show stronger antioxidant activity than the derivatives with mono hydroxy or ortho dihydroxy group. Thus, the ortho hydroxy-amino group can be used as another potential functional group to synthesize novel antioxidants as guessed.
Keywords: The ortho hydroxy-amino group; Antioxidant; BDE; IP;

Spectroscopic studies of the interaction between quercetin and G-quadruplex DNA by Hongxia Sun; Yalin Tang; Junfeng Xiang; Guangzhi Xu; Yazhou Zhang; Hong Zhang; Lianghua Xu (3586-3589).
The different interaction modes of monomeric and dimeric G-quadruplexes with quercetin are reported.Quercetin is a kind of flavonoid which has been proved to exhibit anti-tumor activity. The interaction modes of quercetins with monomeric and dimeric G-quadruplexes were studied by absorption, fluorescence, CD, and 1H NMR spectroscopies. The ligands were found to be stacked with terminal tetrads of monomeric G-quadruplexes by intercalation and bound to dimeric G-quadruplexes by groove binding.
Keywords: G-Quadruplex; Quercetin; Intercalating; Groove binding;

The ability of N-alkyl-N-alkyloxycarbonylaminomethyl promoiety to act as soft alkylating agent and its influence in increasing membrane permeation for phenols, imides and thiols have been probed.Synthesis, characterization and hydrolysis in aqueous buffers of novel N-alkyl-N-alkyloxycarbonylaminomethyl (NANAOCAM) derivatives of substituted phenols, theophylline (Th) and 6-mercaptopurine (6MP) were carried out. The mechanism of hydrolysis was further investigated by synthesis, characterization and hydrolysis of N-aryl-N-alkyloxycarbonylaminomethyl (NArNAOCAM) derivatives of phenols. The hydrolysis follows pseudounimolecular first order kinetics and operates by way of an SN1-type mechanism. Topical delivery of selected derivatives of acetaminophen (APAP), Th and 6MP was examined in in vitro diffusion cell experiments from IPM across hairless mice skins. The prodrug of APAP and 6MP increased permeation across the skin by about 2- and 4-fold, respectively, compared to the parent drug. NANAOCAM promoieties can act as novel prodrug derivatives of phenol, imide and thiol containing drugs for enhancing topical absorption.
Keywords: NANAOCAM; NArNAOCAM; APAP; Th; 6MP; Prodrugs; Dermal delivery;

Design and structure–activity relationship of 3-benzimidazol-2-yl-1H-indazoles as inhibitors of receptor tyrosine kinases by Christopher M. McBride; Paul A. Renhowe; Carla Heise; Johanna M. Jansen; Gena Lapointe; Sylvia Ma; Ramon Piñeda; Jayesh Vora; Marion Wiesmann; Cynthia M. Shafer (3595-3599).
The synthesis and SAR of 3-benzimidazol-2-yl-1H-indazole analogs developed as inhibitors of receptor tyrosine kinases (RTK) is reported.3-Benzimidazol-2-yl-1H-indazole analogs were developed as inhibitors of receptor tyrosine kinases (RTK). The synthesis and SAR of this series is reported.
Keywords: Indazole benzimidazole; Receptor tyrosine kinase (RTK); Vascular endothelial growth factor (VEGF); Basic fibroblast growth factor (bFGF); Platelet derived growth factor (PDGF);

Structure–activity studies of oxazolidinone analogs as RNA-binding agents by John Means; Steven Katz; Abhijit Nayek; Rajaneesh Anupam; Jennifer V. Hines; Stephen C. Bergmeier (3600-3604).
Several oxazolidinone analogs were prepared and examined for binding to two structurally related T box antiterminator model RNAs, AM1A, and AM1A(C11U).We have synthesized and tested a series of novel 3,4,5-tri- and 4,5-disubstituted oxazolidinones for their ability to bind two structurally related T box antiterminator model RNAs. We have found that optimal binding selectivity is found in a small group of 4,5-disubstituted oxazolidinones.
Keywords: Oxazolidinone; RNA; Fluorescence;

Racemic and chiral sulfoxides as potential prodrugs of 4-pyrone COX-2 inhibitors by Francisco Caturla; Mercè Amat; Raquel F. Reinoso; Elena Calaf; Graham Warrellow (3605-3608).
The enantiomeric synthesis and profiling of sulfoxide-based prodrugs of potent COX-2 inhibitors discovered at Almirall are reported.The preparation of the sulfoxide analogues 7, 8, and 9 and their enantiomerically pure forms is discussed as well as their ability to act as prodrugs of the potent and selective sulfone-containing COX-2 inhibitors 1, 2, and 3. Sulfoxide derivatives 7 and 9 were shown to be rapidly transformed in vivo into the corresponding sulfone derivatives 1 and 3, after oral administration to rats.
Keywords: COX-2; Sulfoxides; Prodrugs;

A highly selective κ-opioid receptor agonist with low addictive potential and dependence liability by Hee Sock Park; Hee Yoon Lee; Yong Hae Kim; Jin Kyu Park; Edwin E. Zvartau; Heeseung Lee (3609-3613).
Buprenorphine analogs were synthesized. In the studies of analgesic and addictive effects in mice and [35S]GTPγS binding assay in human brain tissue 16, was identified as a selective κ-partial agonist lacking abuse potential.Buprenorphine analogs have been synthesized. In the studies of analgesic and addictive effects in mice and [35S]GTPγS binding assay in human brain tissue, an analog of buprenorphine where the tert-butyl is replaced by a cyclobutyl moiety (16) has been identified as a selective κ-partial agonist which gives antinociceptive effects, but has low abuse potential. The results may lead to lower degrees of dysphoria than full κ-agonists.
Keywords: κ-partial agonist; Opioid; Addiction; Buprenorphine;

Dipeptidyl nitriles as human dipeptidyl peptidase I inhibitors by Jon Bondebjerg; Henrik Fuglsang; Kirsten Rosendal Valeur; John Pedersen; Lars Nærum (3614-3617).
Using a dipeptide nitrile scaffold we have identified a potent and selective inhibitor of human dipeptidyl peptidase I.
Keywords: Dipeptidyl nitriles; Cathepsin C; Dipeptidyl peptidase I; DPPI; Inflammation; Sepsis;

Erratum to “Synthesis, biological activity, and X-ray crystal structural analysis of diaryl ether inhibitors of malarial enoyl acyl carrier protein reductase. Part 1: 4′-Substituted triclosan derivatives” [Bioorg. Med. Chem. Lett. 15 (2005) 5247–5252] by Joel S. Freundlich; John W. Anderson; Dimitri Sarantakis; Hong-Ming Shieh; Min Yu; Juan-Carlos Valderramos; Edinson Lucumi; Mack Kuo; William R. Jacobs; David A. Fidock; Guy A. Schiehser; David P. Jacobus; James C. Sacchettini (3618-3619).