共查询到20条相似文献,搜索用时 15 毫秒
1.
Starck JP Provins L Christophe B Gillard M Jadot S Lo Brutto P Quéré L Talaga P Guyaux M 《Bioorganic & medicinal chemistry letters》2008,18(8):2675-2678
SAR around alkyne-quinuclidine derivatives allowed the discovery of highly potent muscarinic antagonists displaying interesting preferential slow off-rates from the M3 receptor. 相似文献
2.
Yves Leblanc Patrick Roy Claude Dufresne Nicolas Lachance Zhaoyin Wang Gary O’Neill Gillian Greig Danielle Denis Marie-Claude Mathieu Deborah Slipetz Nicole Sawyer Nancy Tsou 《Bioorganic & medicinal chemistry letters》2009,19(8):2125-2128
Azaindole based structures were evaluated as DP1 receptor antagonists. This work has lead to the discovery of potent, selective and distinct DP1 receptor antagonists. 相似文献
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Wrobleski ML Reichard GA Paliwal S Shah S Tsui HC Duffy RA Lachowicz JE Morgan CA Varty GB Shih NY 《Bioorganic & medicinal chemistry letters》2006,16(14):3859-3863
A series of novel cyclobutane derivatives as potent and selective NK1 receptor antagonists is described. Several compounds in this series exhibited high in vitro binding affinity (Ki 相似文献
5.
Li Qiang T.K. Sasikumar Duane A. Burnett Jing Su Haiqun Tang Yuanzan Ye Robert D. Mazzola Zhaoning Zhu Brian A. McKittrick William J. Greenlee Ahmad Fawzi Michelle Smith Hongtao Zhang Jean E. Lachowicz 《Bioorganic & medicinal chemistry letters》2010,20(3):836-840
A series of novel dopamine D1 antagonists derived from functionalization of the D-ring of SCH 39166 were prepared. A number of these compounds displayed subnanomolar D1 activity and more than 1000-fold selectivity over D2. We found C-3 derivatization afforded compounds with superior overall profile in comparison to the C-2 and C-4 derivatization. A number of highly potent D1 antagonists were discovered which have excellent selectivity over other dopamine receptors and improved PK profile compared to SCH 39166. 相似文献
6.
André Alker Alfred Binggeli Andreas D. Christ Luke Green Hans Peter Maerki Rainer E. Martin Peter Mohr 《Bioorganic & medicinal chemistry letters》2010,20(15):4521-4525
Nicotinamides of benzyl-substituted 4-aminopiperidines and their seven-membered analogs of generic structure 2 and 2′ have been discovered as potent and selective SST5 antagonists. The activity (Ki) ranges from 2.4 to 436 nM. Most compounds exhibit decent physicochemical properties and follow a clear SAR pattern. Interestingly enough, the receptor is strongly enantiodiscriminating and binds in the amino-azepane-series only the (R)-enantiomer. 相似文献
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Shue HJ Chen X Shih NY Blythin DJ Paliwal S Lin L Gu D Schwerdt JH Shah S Reichard GA Piwinski JJ Duffy RA Lachowicz JE Coffin VL Liu F Nomeir AA Morgan CA Varty GB 《Bioorganic & medicinal chemistry letters》2005,15(17):3896-3899
A series of novel five- and six-membered ring urea derivatives have been described as potent and selective NK1 receptor antagonists. Several compounds in this series exhibited good oral activity and brain penetration. Syntheses of these compounds are also described herein. 相似文献
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Pontillo J Tran JA Fleck BA Marinkovic D Arellano M Tucci FC Lanier M Nelson J Parker J Saunders J Murphy B Foster AC Chen C 《Bioorganic & medicinal chemistry letters》2004,14(22):5605-5609
SAR studies of a series of piperazinebenzylamines resulted in the discovery of potent antagonists of the human melanocortin-4 receptor. Compounds 11c, 11d, and 11l, which had K(i) values of 21, 14, and 15 nM, respectively, possessed low efficacy in cAMP stimulation ( approximately 15% of alpha-MSH maximal level) mediated by MC4R, and functioned as antagonists in inhibition of alpha-MSH-stimulated cAMP release in a dose-dependent manner (11l, IC(50)=36 nM). 相似文献
10.
《Bioorganic & medicinal chemistry letters》2020,30(3):126838
A series of indane-type acetamide and propanamide analogues were investigated as TRPV1 antagonists. The analysis of structure–activity relationship indicated that indane A-region analogues exhibited better antagonism than did the corresponding 2,3-dihydrobenzofuran and 1,3-benzodioxole surrogates. Among them, antagonist 36 exhibited potent and selective antagonism toward capsaicin for hTRPV1 and mTRPV1. Further, in vivo studies indicated that antagonist 36 showed excellent analgesic activity in both phases of the formalin mouse pain model and inhibited the pain behavior completely at a dose of 1 mg/kg in the 2nd phase. 相似文献
11.
Shaw AW Paone DV Nguyen DN Stump CA Burgey CS Mosser SD Salvatore CA Rutledge RZ Kane SA Koblan KS Graham SL Vacca JP Williams TM 《Bioorganic & medicinal chemistry letters》2007,17(17):4795-4798
Calcitonin gene-related peptide (CGRP) has been implicated in the pathogenesis of migraine. Replacements for the benzodiazepine core of an earlier lead structure 1 including 5-, 6-, and 7-membered lactams were explored. Within the 7-membered ring scaffold, phenyl substitution at various positions afforded the potent (3R)-amino-(6S)-phenyl caprolactam template. The phenylimidazolinone privileged structure gave additional potency enhancements, as 24 showed good potency in both CGRP binding (K(i)=2 nM) and cAMP (IC(50)=4 nM) assays and was orally bioavailable in rats (27%). 相似文献
12.
Purakkattle Biju Arthur G. Taveras Younong Yu Junying Zheng R. William Hipkin James Fossetta Xuedong Fan Jay Fine Daniel Lundell 《Bioorganic & medicinal chemistry letters》2009,19(5):1434-1437
A series of potent and selective 3,4-diamino-1,2,5-thiadiazoles were prepared and found to show excellent binding affinities towards CXCR2 receptor. 相似文献
13.
Rainer E. Martin Peter Mohr Hans Peter Maerki Wolfgang Guba Christoph Kuratli Olivier Gavelle Alfred Binggeli Stefanie Bendels Rubén Alvarez-Sánchez André Alker Liudmila Polonchuk Andreas D. Christ 《Bioorganic & medicinal chemistry letters》2009,19(21):6106-6113
SAR studies of a recently described SST5R selective benzoxazole piperidine lead series are described with particular focus on the substitution pattern on the benzyl and benzoxazole side-chains. Introduction of a second meta substituent at the benzyl unit significantly lowers residual hH1 activity and insertion of substituents onto the benzoxazole periphery entirely removes remaining h5-HT2B activity. Compounds with single digit nM activity, functional antagonism and favorable physicochemical properties endowed with a good pharmacokinetic profile in rats are described which should become valuable tools for exploring the pharmacological role of the SST5 receptor in vivo. 相似文献
14.
Brian A. Stearns Christopher Baccei Gretchen Bain Alex Broadhead Ryan C. Clark Heather Coate Jilly F. Evans Patrick Fagan John H. Hutchinson Christopher King Catherine Lee Daniel S. Lorrain Peppi Prasit Pat Prodanovich Angelina Santini Jill M. Scott Nicholas S. Stock Yen P. Truong 《Bioorganic & medicinal chemistry letters》2009,19(16):4647-4651
The synthesis of a series of tricyclic antagonists for the prostaglandin D2 receptor DP2 (CRTH2) is disclosed. The activities of the compounds were evaluated in a human DP2 binding assay and a human whole blood eosinophil shape change assay. Potential metabolic liabilities of the compounds were addressed through in vitro CYP studies. The lead compound was demonstrated to have efficacy in a mouse model of allergic rhinitis following oral dosing. 相似文献
15.
Christine Yang Hong C. Shen Zhicai Wu Hong D. Chu Jason M. Cox Jaume Balsells Alejandro Crespo Patricia Brown Beata Zamlynny Judyann Wiltsie Joseph Clemas Jack Gibson Lisa Contino JeanMarie Lisnock Gaochao Zhou Margarita Garcia-Calvo Tom Bateman Ling Xu Peter Sinclair 《Bioorganic & medicinal chemistry letters》2013,23(15):4388-4392
Novel oxazolidinedione analogs were discovered as potent and selective mineralocorticoid receptor (MR) antagonists. Structure–activity relationship (SAR) studies were focused on improving the potency and microsomal stability. Selected compounds demonstrated excellent MR activity, reasonable nuclear hormone receptor selectivity, and acceptable rat pharmacokinetics. 相似文献
16.
Li L Beaulieu C Carriere MC Denis D Greig G Guay D O'Neill G Zamboni R Wang Z 《Bioorganic & medicinal chemistry letters》2010,20(24):7462-7465
We discovered that the introduction of a methyl group to the benzylic position of the N-benzyl group in lead compound 1a has a dramatic effect on improving the binding selectivity of this ligand for the prostanoid receptors DP1 (receptor for prostaglandin D(2)) as compared to TP (receptor for thromboxane A(2)). Based on this discovery, we have synthesized a series of potent and highly selective DP1 antagonists. Among them, compound 1h was identified as a highly selective DP1 antagonist with excellent overall properties. It has a K(i) of 0.43 nM to DP1 in binding assay and an IC(50) of 2.5 nM in the DP1 functional assay. Its selectivity for DP1 over TP (the most potent receptor after DP1) exceeds 750-fold based on both binding and functional assays. These properties make 1h a very potent and highly selective DP1 receptor antagonist suitable for investigating the biological functions of DP1 in normal physiology and models of disease. 相似文献
17.
P J Kukkola N A Bilci T Ikler P Savage S S Shetty D DelGrande A Y Jeng 《Bioorganic & medicinal chemistry letters》2001,11(13):1737-1740
1,3-Disubstituted isoindolines have been discovered as a new class of potent functional ET(A) selective receptor antagonists through pharmacophore analysis of existing nonpeptide endothelin antagonists. The structure-activity relationships for both the trans and the cis series of isoindolines are discussed. 相似文献
18.
Yonghui Wang Jakob Busch-Petersen Feng Wang Terence J. Kiesow Todd L. Graybill Jian Jin Zheng Yang James J. Foley Gerald E. Hunsberger Dulcie B. Schmidt Henry M. Sarau Elizabeth A. Capper-Spudich Zining Wu Laura S. Fisher Michael S. McQueney Ralph A. Rivero Katherine L. Widdowson 《Bioorganic & medicinal chemistry letters》2009,19(1):114-118
A series of N-arylpiperazine camphor sulfonamides was discovered as novel CXCR3 antagonists. The synthesis, structure–activity relationships, and optimization of the initial hit that resulted in the identification of potent and selective CXCR3 antagonists are described. 相似文献
19.
Perron-Sierra F Saint Dizier D Bertrand M Genton A Tucker GC Casara P 《Bioorganic & medicinal chemistry letters》2002,12(22):3291-3296
A novel series of potent and specific alpha(v) integrin antagonists has been obtained by aminoalkyl substitutions on benzocyloheptene acetic acids as a rigid GD bioisostere. The preferred compounds 1-2, 1-3 and 1-8, showed nano- to subnanomolar IC(50) values on alpha(v)beta(3) and alpha(v)beta(5) integrins, with favorable pharmacokinetics. 相似文献
20.
Birkinshaw TN Teague SJ Beech C Bonnert RV Hill S Patel A Reakes S Sanganee H Dougall IG Phillips TT Salter S Schmidt J Arrowsmith EC Carrillo JJ Bell FM Paine SW Weaver R 《Bioorganic & medicinal chemistry letters》2006,16(16):4287-4290
Starting with the weak agonist indomethacin, a series of potent, selective CRTh2 (DP(2)) antagonists have been discovered as potential treatments for asthma, allergic rhinitis and other inflammatory diseases. 相似文献