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Betageri R Zhang Y Zindell RM Kuzmich D Kirrane TM Bentzien J Cardozo M Capolino AJ Fadra TN Nelson RM Paw Z Shih DT Shih CK Zuvela-Jelaska L Nabozny G Thomson DS 《Bioorganic & medicinal chemistry letters》2005,15(21):4761-4769
Compound 1, a potent glucocorticoid receptor ligand, contains a quaternary carbon bearing trifluoromethyl and hydroxyl groups. This paper describes the effect of replacing the trifluoromethyl group on binding and agonist activity of the GR ligand 1. The results illustrate that replacing the CF3 group with a cyclohexylmethyl or benzyl group maintains the GR binding potency. These substitutions alter the functional behavior of the GR ligands from agonists to antagonists. Docking studies suggest that the benzyl analog 19 binds in a similar fashion as the GR antagonist, RU486. The central benzyl group of 19 and the C-11 dimethylaniline moiety of RU486 overlay. Binding of compound 19 is believed to force helix 12 to adopt an open conformation and this leads to the antagonist properties of the non-CF3 ligands carrying a large group at the center of the molecule. 相似文献
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Hammach A Barbosa A Gaenzler FC Fadra T Goldberg D Hao MH Kroe RR Liu P Qian KC Ralph M Sarko C Soleymanzadeh F Moss N 《Bioorganic & medicinal chemistry letters》2006,16(24):6316-6320
A new class of benzimidazolone p38 MAP kinase inhibitors was discovered through high-throughput screening. X-ray crystallographic data of the lead molecule with p38 were used to design analogues with improved binding affinity and potency in a cell assay of LPS-induced TNF production. Herein, we report the SAR of this new class of p38 inhibitors. 相似文献
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Pier F. Cirillo Eugene R. Hickey Neil Moss Steffen Breitfelder Raj Betageri Tazmeen Fadra Faith Gaenzler Thomas Gilmore Daniel R. Goldberg Victor Kamhi Thomas Kirrane Rachel R. Kroe Jeffrey Madwed Monica Moriak Matthew Netherton Christopher A. Pargellis Usha R. Patel Kevin C. Qian Rajiv Sharma Sanxing Sun Zhaoming Xiong 《Bioorganic & medicinal chemistry letters》2009,19(9):2386-2391
An effort aimed at exploring structural diversity in the N-pyrazole-N′-naphthylurea class of p38 kinase inhibitors led to the synthesis and characterization of N-phenyl-N′-naphthylureas. Examples of these compounds displayed excellent inhibition of TNF-α production in vitro, as well as efficacy in a mouse model of lipopolysaccharide induced endotoxemia. In addition, perspective is provided on the role of a sulfonamide functionality in defining inhibitor potency. 相似文献
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Daniel Kuzmich Jörg Bentzien Raj Betageri Darren DiSalvo Tazmeen Fadra-Khan Christian Harcken Alison Kukulka Gerald Nabozny Richard Nelson Edward Pack Donald Souza David Thomson 《Bioorganic & medicinal chemistry letters》2013,23(24):6640-6644
A class of α-methyltryptamine sulfonamide glucocorticoid receptor (GR) modulators was optimized for agonist activity. The design of ligands was aided by molecular modeling, and key function-regulating pharmacophoric points were identified that are critical in achieving the desired agonist effect in cell based assays. Compound 27 was profiled in vitro and in vivo in models of inflammation. Analogs could be rapidly prepared in a parallel approach from aziridine building blocks. 相似文献
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Darren DiSalvo Daniel Kuzmich Jörg Bentzien John Regan Alison Kukulka Tazmeen Fadra-Khan Richard Nelson Christian Harcken David Thomson Gerald Nabozny 《Bioorganic & medicinal chemistry letters》2013,23(24):6645-6649
A class of arylsulfonamide glucocorticoid receptor agonists that contains a substituted phenyl group as a steroid A-ring mimetic is reported. The structural design and SAR that provide the functional switching of a GR antagonist to an agonist is described. A combination of specific hydrogen bonding and lipophilic elements on the A-ring moiety is required to achieve potent GR agonist activity. This study culminated in the identification of compound 23 as a potent GR agonist with selectivity over the PR and MR nuclear hormone receptors. 相似文献
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Betageri R Gilmore T Kuzmich D Kirrane TM Bentzien J Wiedenmayer D Bekkali Y Regan J Berry A Latli B Kukulka AJ Fadra TN Nelson RM Goldrick S Zuvela-Jelaska L Souza D Pelletier J Dinallo R Panzenbeck M Torcellini C Lee H Pack E Harcken C Nabozny G Thomson DS 《Bioorganic & medicinal chemistry letters》2011,21(22):6842-6851
We report a SAR of non-steroidal glucocorticoid mimetics that utilize indoles as A-ring mimetics. Detailed SAR is discussed with a focus on improving PR and MR selectivity, GR agonism, and in vitro dissociation profile. SAR analysis led to compound (R)-33 which showed high PR and MR selectivity, potent agonist activity, and reduced transactivation activity in the MMTV and aromatase assays. The compound is equipotent to prednisolone in the LPS-TNF model of inflammation. In mouse CIA, at 30 mg/kg compound (R)-33 inhibited disease progression with an efficacy similar to the 3 mg/kg dose of prednisolone. 相似文献
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New modifications to the area of pyrazole-naphthyl urea based p38 MAP kinase inhibitors that bind to the adenine/ATP site 总被引:1,自引:0,他引:1
Moss N Breitfelder S Betageri R Cirillo PF Fadra T Hickey ER Kirrane T Kroe RR Madwed J Nelson RM Pargellis CA Qian KC Regan J Swinamer A Torcellini C 《Bioorganic & medicinal chemistry letters》2007,17(15):4242-4247
Discovery of the pyrazole-naphthyl urea class of p38 MAP kinase inhibitors typified by the clinical candidate BIRB 796 has encouraged further exploration of this particular scaffold. Modification to the part of the inhibitor that occupies the adenine/ATP binding site has resulted in a new way to obtain potent inhibitors that possess favorable in vitro and in vivo properties. 相似文献
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