共查询到20条相似文献,搜索用时 0 毫秒
1.
Nian Zhou Alexandre M. Polozov Matthew O’Connell James Burgeson Peng Yu Wayne Zeller Jun Zhang Emmanuel Onua Jose Ramirez Gudrun A. Palsdottir Gudrun V. Halldorsdottir Thorkell Andresson Alex S. Kiselyov Mark Gurney Jasbir Singh 《Bioorganic & medicinal chemistry letters》2010,20(8):2658-2664
A series of novel 1,7-disubstituted oxyindoles were shown to be potent and selective EP3 receptor antagonists. Variation of substitution pattern at the C-3 position of indole enhanced in vitro metabolic stability of the resulting derivatives. Series 27a–c showed >1000-fold selectivity over a panel of prostanoid receptors including IP, FP, EP1, EP2 and EP4. These agents also featured low CYP inhibition and good activity in the functional rat platelet aggregation assay. 相似文献
2.
Nian Zhou Wayne Zeller Michael Krohn Herb Anderson Jun Zhang Emmanuel Onua Alex S. Kiselyov Jose Ramirez Guðrún Halldorsdottir Þorkell Andrésson Mark E. Gurney Jasbir Singh 《Bioorganic & medicinal chemistry letters》2009,19(1):123-126
A series of potent and selective EP3 receptor antagonists are described. Utilizing a pharmacophore model developed for the EP3 receptor, a series of 3,4-disubstituted indoles were shown to be high affinity ligands for this target. These compounds showed high selectivity over IP, FP and other EP receptors and are potent antagonists in functional assays. 相似文献
3.
Matthew O’Connell Wayne Zeller James Burgeson Rama K. Mishra Jose Ramirez Alex S. Kiselyov Þorkell Andrésson Mark E. Gurney Jasbir Singh 《Bioorganic & medicinal chemistry letters》2009,19(3):778-782
A series of peri-substituted [4.3.0] bicyclic non-aromatic heterocycles have been identified as potent and selective hEP3 receptor antagonists. These molecules adopt a hair-pin conformation that overlaps with the endogenous ligand PGE2 and fits into an internally generated EP3 pharmacophore model. Optimized compounds show good metabolic stability and improved solubility over their corresponding bicyclic aromatic analogs. 相似文献
4.
Naganawa A Matsui T Saito T Ima M Tatsumi T Yamamoto S Murota M Yamamoto H Maruyama T Ohuchida S Nakai H Kondo K Toda M 《Bioorganic & medicinal chemistry》2006,14(19):6628-6639
4-({2-[Isobutyl(phenylsulfonyl)amino]-5-(trifluoromethyl)phenoxy}methyl)benzoic acid (1) is a functional PGE2 antagonist selective for EP1 receptor subtype. Analogs of 1, in which the phenyl-sulfonyl moiety has been replaced with more hydrophilic heteroarylsulfonyl moieties, exhibited more optimized antagonist activity, while some of them showed in vivo antagonist activity. Structure-activity relationship (SAR) studies are also presented. 相似文献
5.
Masaki Asada Tetsuo Obitsu Atsushi Kinoshita Yoshihiko Nakai Toshihiko Nagase Isamu Sugimoto Motoyuki Tanaka Hiroya Takizawa Ken Yoshikawa Kazutoyo Sato Masami Narita Shuichi Ohuchida Hisao Nakai Masaaki Toda 《Bioorganic & medicinal chemistry letters》2010,20(8):2639-2643
A series of novel N-acylsulfonamide analogs were synthesized and evaluated for their binding affinity and antagonist activity for the EP3 receptor subtype. Representative compounds were also evaluated for their inhibitory effect on PGE2-induced uterine contraction in pregnant rats. Among those tested, a series of N-acylbenzenesulfonamide analogs were found to be more potent than the corresponding carboxylic acid analogs in both the in vitro and in vivo evaluations. The structure activity relationships (SAR) are also discussed. 相似文献
6.
Bromidge SM Clarke SE King FD Lovell PJ Newman H Riley G Routledge C Serafinowska HT Smith DR Thomas DR 《Bioorganic & medicinal chemistry letters》2002,12(10):1357-1360
The synthesis of novel 3-(octahydropyrido[1,2-a]pyrazin-2-yl)- and 3-(hexahydropyrrolo[1,2-a]pyrazin-2-yl)phenyl-2-benzo[b]thiophene sulphonamide derivatives 3, (S)-4 and (R)-4 is described. The compounds show high affinity for the 5-HT6 receptor, excellent selectivity against a range of other receptors and good brain penetration. 相似文献
7.
Li YH Tseng PS Evans KA Jaworski JP Morrow DM Fries HE Wu CW Edwards RM Jin J 《Bioorganic & medicinal chemistry letters》2010,20(22):6744-6747
A series of 3-urea-1-(phenylmethyl)-pyridones was discovered as novel EP(3) antagonists via high-throughput screening and subsequent optimization. The synthesis, structure-activity relationships, and optimization of the initial hit that resulted in potent and selective EP(3) receptor antagonists such as 11g are described. 相似文献
8.
Qingyian Liu Wenyuan Qian Aiwen Li Kaustav Biswas Jian Jeffrey Chen Christopher Fotsch Nianhe Han Chester Yuan Leyla Arik Gloria Biddlecome Eileen Johnson Gondi Kumar Dianna Lester-Zeiner Gordon Y. Ng Randall W. Hungate Benny C. Askew 《Bioorganic & medicinal chemistry letters》2010,20(15):4593-4597
The bradykinin B1 receptor has been shown to mediate pain response and is rapidly induced upon injury. Blocking this receptor may provide a promising treatment for inflammation and pain. We previously reported tetralin benzyl amines as potent B1 antagonists. Here we describe the synthesis and SAR of B1 receptor antagonists with homobenzylic amines. The SAR of different linkers led to the discovery of tetralin allylic amines as potent and selective B1 receptor antagonists (hB1 IC50 = 1.3 nM for compound 16). Some of these compounds showed modest oral bioavailability in rats. 相似文献
9.
Nian Zhou Wayne Zeller Jun Zhang Emmanuel Onua Alex S. Kiselyov Jose Ramirez Guðrún Palsdottir Guðrún Halldorsdottir Þorkell Andrésson Mark E. Gurney Jasbir Singh 《Bioorganic & medicinal chemistry letters》2009,19(5):1528-1531
A series of potent and selective EP3 receptor antagonists are described. Utilizing a pharmacophore model developed for the EP3 receptor, a series of 3,4-disubstituted indoles were found to be efficient ligands for this target. These compounds showed high selectivity over IP, FP and other EP receptors. An optimized molecule 7c featured a sound profile and potency in the functional rat and human platelet aggregation assays. 相似文献
10.
Mark A. Hilfiker Ning Wang Xiaoping Hou Zhimin Du Mark A. Pullen Melanie Nord Rakesh Nagilla Harvey E. Fries Charlene W. Wu Anthony C. Sulpizio Jon-Paul Jaworski Dwight Morrow Richard M. Edwards Jian Jin 《Bioorganic & medicinal chemistry letters》2009,19(15):4292-4295
This Letter discloses a series of 2-aminothiadiazole amides as selective EP3 receptor antagonists. SAR optimization resulted in compounds with excellent functional activity in vitro. In addition, efforts to optimize DMPK properties in the rat are discussed. These efforts have resulted in the identification of potent, selective EP3 receptor antagonists with excellent DMPK properties suitable for in vivo studies. 相似文献
11.
Burch JD Farand J Colucci J Sturino C Ducharme Y Friesen RW Lévesque JF Gagné S Wrona M Therien AG Mathieu MC Denis D Vigneault E Xu D Clark P Rowland S Han Y 《Bioorganic & medicinal chemistry letters》2011,21(3):1041-1046
Two new series of EP4 antagonists based on naphthalene/quinoline scaffolds have been identified as part of our on-going efforts to develop treatments for inflammatory pain. One series contains an acidic sulfonylurea pharmacophore, whereas the other is a neutral amide. Both series show subnanomolar intrinsic binding potency towards the EP4 receptor, and excellent selectivity towards other prostanoid receptors. While the amide series generally displays poor pharmacokinetic parameters, the sulfonylureas exhibit greatly improved profile. MF-592, the optimal compound from the sulfonylurea series, has a desirable overall preclinical profile that suggests it is suitable for further development. 相似文献
12.
Ducharme Y Blouin M Carrière MC Chateauneuf A Côté B Denis D Frenette R Greig G Kargman S Lamontagne S Martins E Nantel F O'Neill G Sawyer N Metters KM Friesen RW 《Bioorganic & medicinal chemistry letters》2005,15(4):1155-1160
The synthesis and the EP(1) receptor binding affinity of 2,3-diarylthiophene derivatives are described. The evaluation of the structure-activity relationship (SAR) in this series led to the identification of compounds 4, 7, and 12a, which exhibit high affinity for the human EP(1) receptor and a selectivity greater than 100-fold against the EP(2), EP(3), EP(4), DP, FP, and IP receptors and greater than 25-fold versus the TP receptor. These three antagonists present good pharmacokinetics in rats and significant differences in the way they are distributed in the brain. 相似文献
13.
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
14.
Zaghdane H Boyd M Colucci J Simard D Berthelette C Leblanc Y Wang Z Houle R Lévesque JF Molinaro C Hamel M Stocco R Sawyer N Sillaots S Gervais F Gallant M 《Bioorganic & medicinal chemistry letters》2011,21(11):3471-3474
A new series of indole amide acting as hCRTH2 receptor ligands had been explored and are described herein. Several amide derivatives displaying low nanomolar activity in hCRTH2 binding and whole blood assays were identified. They were found to behave as a full antagonists, exhibiting good selectivity over related prostaglandin receptors. Also, prototypical compounds in this novel series which displayed acceptable CYP profiles and were orally bioavailable in rats were identified. 相似文献
15.
Jung KY Kim SK Gao ZG Gross AS Melman N Jacobson KA Kim YC 《Bioorganic & medicinal chemistry》2004,12(3):613-623
4-(4-Methoxyphenyl)-2-aminothiazole and 3-(4-methoxyphenyl)-5-aminothiadiazole derivatives have been synthesized and evaluated as selective antagonists for human adenosine A3 receptors. A methoxy group in the 4-position of the phenyl ring and N-acetyl or propionyl substitutions of the aminothiazole and aminothiadiazole templates displayed great increases of binding affinity and selectivity for human adenosine A3 receptors. The most potent A3 antagonist of the present series, N-[3-(4-methoxy-phenyl)-[1,2,4]thiadiazol-5-yl]-acetamide (39) exhibiting a Ki value of 0.79 nM at human adenosine A3 receptors, showed antagonistic property in a functional assay of cAMP biosynthesis involved in one of the signal transduction pathways of adenosine A3 receptors. Molecular modeling study of conformation search and receptor docking experiments to investigate the dramatic differences of binding affinities between two regioisomers of thiadiazole analogues, (39) and (42), suggested possible binding mechanisms in the binding pockets of adenosine receptors. 相似文献
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18.
Chenard BL Menniti FS Pagnozzi MJ Shenk KD Ewing FE Welch WM 《Bioorganic & medicinal chemistry letters》2000,10(11):1203-1205
Quinazolin-4-one derivatives of methaqualone substituted at C-2 define a new class of noncompetitive antagonists at AMPA receptors. 相似文献
19.
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
20.
Fujimoto T Tomata Y Kunitomo J Hirozane M Marui S 《Bioorganic & medicinal chemistry letters》2011,21(21):6409-6413
To generate novel human Orexin-2 Receptor (OX2R) antagonists, a spiropiperidine based scaffold was designed and a SAR study was carried out. Compound 4f possessed the highest OX2R antagonistic activity with an IC(50) value of 3nM with 450-fold selectivity against Orexin-1 Receptor (OX1R). 相似文献