共查询到20条相似文献,搜索用时 0 毫秒
1.
Paul J. Coleman John D. Schreier Georgia B. McGaughey Michael J. Bogusky Christopher D. Cox George D. Hartman Richard G. Ball C. Meacham Harrell Duane R. Reiss Thomayant Prueksaritanont Christopher J. Winrow John J. Renger 《Bioorganic & medicinal chemistry letters》2010,20(7):2311-2315
Orexins are neuropeptides that regulate wakefulness and arousal. Small molecule antagonists of orexin receptors may provide a novel therapy for the treatment of insomnia and other sleep disorders. In this Letter we describe the design and synthesis of conformationally constrained N,N-disubstituted 1,4-diazepanes as orexin receptor antagonists. The design of these constrained analogs was guided by an understanding of the preferred solution and solid state conformation of the diazepane central ring. 相似文献
2.
《Bioorganic & medicinal chemistry letters》2019,29(15):1974-1980
A novel series of indazole/indole derivatives were discovered as glucagon receptor (GCGR) antagonists through scaffold hopping based on two literature leads: MK-0893 and LY-2409021. Further structure-activity relationship (SAR) exploration and optimization led to the discovery of multiple potent GCGR antagonists with excellent pharmacokinetic properties in mice and rats, including low systemic clearance, long elimination half-life, and good oral bioavailability. These potent GCGR antagonists could be used for potential treatment of type II diabetes. 相似文献
3.
《Bioorganic & medicinal chemistry letters》2014,24(3):839-844
Identification of orally active, small molecule antagonists of the glucagon receptor represents a novel treatment paradigm for the management of type 2 diabetes mellitus. The present work discloses novel glucagon receptor antagonists, identified via conformational constraint of current existing literature antagonists. Optimization of lipophilic ligand efficiency (LLE or LipE) culminated in enantiomers (+)-trans-26 and (−)-trans-27 which exhibit good physicochemical and in vitro drug metabolism profiles. In vivo, significant pharmacokinetic differences were noted with the two enantiomers, which were primarily driven through differences in clearance rates. Enantioselective oxidation by cytochrome P450 was ruled out as a causative factor for pharmacokinetic differences. 相似文献
4.
Guo T Gu H Hobbs DW Busler DE Rokosz LL 《Bioorganic & medicinal chemistry letters》2007,17(6):1718-1721
Melanin concentrating hormone (MCH) plays an important role in the regulation of food intake and energy balance in mammals. MCH-1 receptor (MCH1R) deficient mice are lean and resistant to diet-induced obesity. As such, MCH1R antagonists are believed to have potential as possible treatments for obesity. The discovery of a novel class of tetralin ureas as potent MCH1R antagonists is described herein. 相似文献
5.
Urbahns K Härter M Vaupel A Albers M Schmidt D Brüggemeier U Stelte-Ludwig B Gerdes C Tsujishita H 《Bioorganic & medicinal chemistry letters》2003,13(6):1071-1074
Vitronectin receptor (alpha(V)beta(3)) antagonism has been implicated in a variety of disease states, like restenosis, osteoporosis and cancer. In this work, we present the development of a novel class of biphenyl vitronectin receptor antagonists. Identified from a focused combinatorial library based on para-bromo phenylalanine, these compounds show nanomolar affinity to the vitronectin receptor and display unprecedented SAR. Their binding mode can be rationalized by computational docking studies using the X-ray structure of alpha(V)beta(3). 相似文献
6.
Sinz C Chang J Lins AR Brady E Candelore M Dallas-Yang Q Ding V Jiang G Lin Z Mock S Qureshi S Salituro G Saperstein R Shang J Szalkowski D Tota L Vincent S Wright M Xu S Yang X Zhang B Tata J Kim R Parmee E 《Bioorganic & medicinal chemistry letters》2011,21(23):7131-7136
In the course of the development of an aminobenzimidazole class of human glucagon receptor (hGCGR) antagonists, a novel class of cyclic guanidine hGCGR antagonists was discovered. Rapid N-dealkylation resulted in poor pharmacokinetic profiles for the benchmark compound in this series. A strategy aimed at blocking oxidative dealkylation led to a series of compounds with improved rodent pharmacokinetic profiles. One compound was orally efficacious in a murine glucagon challenge pharmacodynamic model and also significantly lowered glucose levels in a murine diabetes model. 相似文献
7.
Hojung Choi Chang-Yong Lee Eun-Young Park Kyoung Mee Lee Dongyun Shin Hee-Sook Jun 《Bioorganic & medicinal chemistry》2018,26(21):5701-5710
The hormone glucagon increases blood glucose levels through increasing hepatic glucose output. In diabetic patients, dysregulation of glucagon secretion contributes to hyperglycemia. Thus, the inhibition of glucagon receptor is one target for the treatment of hyperglycemia in type 2 diabetes. Here we designed and synthesized a series of small molecules based on phenylpyrimidine. Of these, the compound (R)-7a most significantly decreased the glucagon-induced cAMP production and glucagon-induced glucose production during in vitro and in vivo assays. In addition, (R)-7a showed good efficacy in glucagon challenge tests and lowered blood glucose levels in diabetic db/db mice. Our results suggest that the compound (R)-7a could be a potential glucose-lowering agent for treating type 2 diabetes. 相似文献
8.
Schmidt RG Bayburt EK Latshaw SP Koenig JR Daanen JF McDonald HA Bianchi BR Zhong C Joshi S Honore P Marsh KC Lee CH Faltynek CR Gomtsyan A 《Bioorganic & medicinal chemistry letters》2011,21(5):1338-1341
Novel chroman and tetrahydroquinoline ureas were synthesized and evaluated for their activity as TRPV1 antagonists. It was found that aryl substituents on the 7- or 8-position of both bicyclic scaffolds imparted the best in vitro potency at TRPV1. The most potent chroman ureas were assessed in chronic and acute pain models, and compounds with the ability to cross the blood-brain barrier were shown to be highly efficacious. The tetrahydroquinoline ureas were found to be potent CYP3A4 inhibitors, but replacement of bulky substituents at the nitrogen atom of the tetrahydroisoquinoline moiety with small groups such as methyl can minimize the inhibition. 相似文献
9.
R S Struthers G Tanaka S C Koerber T Solmajer E L Baniak L M Gierasch W Vale J Rivier A T Hagler 《Proteins》1990,8(4):295-304
The introduction of conformational constraints into a flexible peptide hormone can be exploited to develop models for the conformation required for receptor binding and activity. In this review, we illustrate this approach to analog design using our work on antagonists of gonadotropin-releasing hormone (GnRH). Design of a conformationally constrained, competitive antagonist of GnRH, cyclo[delta 3,4 Pro-D4ClPhe-DTrp-Ser-Tyr-DTrp-NMeLeu-Arg-Pro-bet a Ala] led to the prediction of its bioactive conformation. Template forcing experiments show that this conformation is accessible to other active GnRH analogs. Two-dimensional NMR studies verified the predicted conformation in solution. The predicted binding conformation has recently been used to design two new analogs incorporating side chain-side chain linkages suggested by the conformational model: Ac-delta 3,4Pro-D4FPhe-DTrp-Dap-Tyr-DTrp-Leu-Arg-Asp-Gly- NH2 and Ac-delta 3,4Pro-D4FPhe-DTrp-Dap-Tyr-D2Nal-Leu-Arg-Pro-Asp -NH2. These analogs were synthesized and the one predicted to be most similar to the parent conformation had equivalent potency while the second, designed to refine the conformational hypothesis, was found to exhibit enhanced potency, thus confirming the original binding conformation hypothesis. These compounds and their derivatives now provide a new class of GnRH antagonists possessing both high biological potency and limited conformational flexibility, thus making them ideal for both biophysical and structure-activity studies. 相似文献
10.
Discovery of novel, potent, and orally active spiro-urea human glucagon receptor antagonists 总被引:4,自引:0,他引:4
Shen DM Zhang F Brady EJ Candelore MR Dallas-Yang Q Ding VD Dragovic J Feeney WP Jiang G McCann PE Mock S Qureshi SA Saperstein R Shen X Tamvakopoulos C Tong X Tota LM Wright MJ Yang X Zheng S Chapman KT Zhang BB Tata JR Parmee ER 《Bioorganic & medicinal chemistry letters》2005,15(20):4564-4569
A novel class of spiro-ureas has been discovered as potent human glucagon receptor antagonists in both binding and functional assays. Preliminary studies have revealed that compound 15 is an orally active human glucagon receptor antagonist in a transgenic murine pharmacodynamic model at 10 and 30 mpk. Compound 15 is orally bioavailable in several preclinical species and shows selectivity toward cardiac ion channels and other family B receptors, such as hGIP1 and hGLP. 相似文献
11.
Craig A. Stump Ian M. Bell Rodney A. Bednar John F. Fay Steven N. Gallicchio James C. Hershey Richard Jelley Constantine Kreatsoulas Eric L. Moore Scott D. Mosser Amy G. Quigley Shane A. Roller Christopher A. Salvatore Steven S. Sharik Cory R. Theberge C. Blair Zartman Stefanie A. Kane Samuel L. Graham Harold G. Selnick Joseph P. Vacca Theresa M. Williams 《Bioorganic & medicinal chemistry letters》2010,20(8):2572-2576
A novel series of potent CGRP receptor antagonists containing a central quinoline ring constraint was identified. The combination of the quinoline constraint with a tricyclic benzimidazolinone left hand fragment produced an analog with picomolar potency (14, CGRP Ki = 23 pM). Further optimization of the tricycle produced a CGRP receptor antagonist that exhibited subnanomolar potency (19, CGRP Ki = 0.52 nM) and displayed a good pharmacokinetic profile in three preclinical species. 相似文献
12.
Shuangjie Shu Antao Dai Jiang Wang Bin Wang Yang Feng Jia Li Xiaoqing Cai Dehua Yang Dakota Ma Ming-Wei Wang Hong Liu 《Bioorganic & medicinal chemistry》2018,26(8):1896-1908
A novel series of 4-methyl substituted pyrazole derivatives were designed, synthesized and biologically evaluated as potent glucagon receptor (GCGR) antagonists. In this study, compounds 9q, 9r, 19d and 19e showed high GCGR binding (IC50?=?0.09?μM, 0.06?μM, 0.07?μM and 0.08?μM, respectively) and cyclic-adenosine monophosphate (cAMP) activities (IC50?=?0.22?μM, 0.26?μM, 0.44?μM and 0.46?μM, respectively) in cell-based assays. Most importantly, the docking experiment demonstrated that compound 9r formed extensive hydrophobic interactions with the receptor binding pocket, making it justifiable to further investigate the potential of becoming a GCGR antagonist. 相似文献
13.
Wang Y Chackalamannil S Chang W Greenlee W Ruperto V Duffy RA McQuade R Lachowicz JE 《Bioorganic & medicinal chemistry letters》2001,11(7):891-894
Novel, selective M2 muscarinic antagonists, which replace the metabolically labile styrenyl moiety of the prototypical M2 antagonist 1 with an ether linkage, were synthesized. A detailed SAR study in this class of compounds has yielded highly active compounds that showed M2 Ki values of < 1.0 nM and >100-fold selectivity against M1, M3, and M5 receptors. 相似文献
14.
Kim RM Chang J Lins AR Brady E Candelore MR Dallas-Yang Q Ding V Dragovic J Iliff S Jiang G Mock S Qureshi S Saperstein R Szalkowski D Tamvakopoulos C Tota L Wright M Yang X Tata JR Chapman K Zhang BB Parmee ER 《Bioorganic & medicinal chemistry letters》2008,18(13):3701-3705
The discovery and optimization of potent and selective aminobenzimidazole glucagon receptor antagonists are described. One compound possessing moderate pharmacokinetic properties in multiple preclinical species was orally efficacious at inhibiting glucagon-mediated glucose excursion in transgenic mice expressing the human glucagon receptor, and in rhesus monkeys. The compound also significantly lowered glucose levels in a murine model of diabetes. 相似文献
15.
Grey J Dyck B Rowbottom MW Tamiya J Vickers TD Zhang M Zhao L Heise CE Schwarz D Saunders J Goodfellow VS 《Bioorganic & medicinal chemistry letters》2005,15(4):999-1004
Ureas derived from two substituted 3-aminopyrrolidine subunits were prepared as constrained analogs of a linear lead compound and tested as antagonists of the MCH(1) receptor. The series was optimized for substitution and stereochemistry to generate a functional antagonist with a K(i) of 3.3 nM and IC(50) of 12 nM (GTPgammaS). 相似文献
16.
《Bioorganic & medicinal chemistry》2016,24(12):2852-2863
Glucagon receptor antagonists possess a great potential for treatment of type 2 diabetes mellitus. A series of pyrazole-containing derivatives were designed, synthesized and evaluated by biological assays as glucagon receptor antagonists. Most of the compounds exhibited good in vitro efficacy. Two of them, compounds 17f and 17k, displayed relatively potent antagonist effects on glucagon receptors with IC50 values of 3.9 and 3.6 μM, respectively. The possible binding modes of 17f and 17k with the cognate receptor were explored by molecular docking simulation. 相似文献
17.
Jiang W Tucci FC Tran JA Fleck BA Wen J Markison S Marinkovic D Chen CW Arellano M Hoare SR Johns M Foster AC Saunders J Chen C 《Bioorganic & medicinal chemistry letters》2007,17(20):5610-5613
A series of pyrrolidinones derived from phenylalaninepiperazines were synthesized and characterized as potent and selective antagonists of the melanocortin-4 receptor. In addition to their high binding affinities, these compounds displayed high functional potencies. 12a had a K(i) of 0.94 nM in binding and IC(50) of 21 nM in functional activity. 12a also demonstrated efficacy in a mouse cachexia model. 相似文献
18.
Wang Y Chackalamannil S Hu Z Clader JW Greenlee W Billard W Binch H Crosby G Ruperto V Duffy RA McQuade R Lachowicz JE 《Bioorganic & medicinal chemistry letters》2000,10(20):2247-2250
Identification of a number of highly potent M2 receptor antagonists with >100-fold selectivity against the M1 and M3 receptor subtypes is described. In the rat microdialysis assay, this series of compounds showed pronounced enhancement of brain acetylcholine release after oral administration. 相似文献
19.
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
20.
L L Chang K L Sidler M A Cascieri S de Laszlo G Koch B Li M MacCoss N Mantlo S O'Keefe M Pang A Rolando W K Hagmann 《Bioorganic & medicinal chemistry letters》2001,11(18):2549-2553
A modestly active, nonselective triarylimidazole lead was optimized for binding affinity with the human glucagon receptor. This led to the identification of a 2- and/or 4-alkyl or alkyloxy substituent on the imidazole C4-aryl group as a structural determinant for significant enhancement in binding with the glucagon receptor (e.g., 41, IC(50)=0.053 microM) and selectivity (>1000x) over p38MAP kinase in this class of compounds. 相似文献