共查询到20条相似文献,搜索用时 0 毫秒
1.
Masaki Asada Tetsuo Obitsu Toshihiko Nagase Motoyuki Tanaka Yoshiyuki Yamaura Hiroya Takizawa Ken Yoshikawa Kazutoyo Sato Masami Narita Shuichi Ohuchida Hisao Nakai Masaaki Toda 《Bioorganic & medicinal chemistry》2010,18(1):80-90
A series of 3-(2-aminocarbonyl-4-phenoxymethylphenyl)propanoic acid analogs were synthesized and evaluated for their EP3 antagonist activity in the presence of additive serum albumin. Several compounds were biologically evaluated for their in vivo efficacy with respect to the PGE2-induced uterine contraction in pregnant rats as well as their pharmacokinetics. The discovery process of these potent and selective EP3 antagonists and their structure activity relationship are also presented. 相似文献
2.
Masaki Asada Tetsuo Obitsu Atsushi Kinoshita Toshihiko Nagase Tadahiro Yoshida Yoshiyuki Yamaura Hiroya Takizawa Ken Yoshikawa Kazutoyo Sato Masami Narita Hisao Nakai Masaaki Toda Yoshito Tobe 《Bioorganic & medicinal chemistry》2010,18(9):3212-3223
A series of 3-(2-aminocarbonylphenyl)propanoic acid analogs possessing the (1R)-1-(3,5-dimethylphenyl)-3-methylbutylamine moiety on the carboxyamide side chain were synthesized and evaluated for their binding affinity for the EP1-4 receptors and their antagonist activity for the EP3 receptor. Rational drug design based on the structure of the metabolites in human liver microsomes led us to the discovery of another series of analogs. Several compounds were further evaluated for their in vivo efficacy in rats after oral administration and also for their pharmacokinetic profiles including in vitro stability in the liver microsomes. 相似文献
3.
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
4.
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
5.
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
6.
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
7.
Discovery of novel prostaglandin analogs of PGE2 as potent and selective EP2 and EP4 receptor agonists 总被引:1,自引:0,他引:1
Xiao Y Araldi GL Zhao Z Brugger N Karra S Fischer D Palmer E 《Bioorganic & medicinal chemistry letters》2007,17(15):4323-4327
Analogs of PGE(2) with introduction of diene groups at the omega-side chain have been synthesized and evaluated for their binding affinity for EP(2) and EP(4) receptors. An optimized analog (compound 9b) showed high potency and selectivity for the EP(4) receptor over other known receptors. 相似文献
8.
Wang Y Chackalamannil S Hu Z McKittrick BA Greenlee W Ruperto V Duffy RA Lachowicz JE 《Bioorganic & medicinal chemistry letters》2002,12(7):1087-1091
We have discovered highly potent, selective sulfide M(2) receptor antagonists with low molecular weight and different structural features compared with our phase I clinical candidate Sch 211803. Analogue 30 showed superior M(2) receptor selectivity profile over Sch 211803. More importantly, this study provided new leads for the discovery of M(2) receptor antagonists as potential drug candidates. 相似文献
9.
Dhanak D Christmann LT Darcy MG Keenan RM Knight SD Lee J Ridgers LH Sarau HM Shah DH White JR Zhang L 《Bioorganic & medicinal chemistry letters》2001,11(11):1445-1450
Highly potent CCR3 antagonists have been developed from a previously reported series of phenylalanine ester-based leads. Solution-phase, parallel synthesis optimization was utilized to identify highly potent, functional CCR3 antagonists. 相似文献
10.
Georgeta Hategan Alexandre M. Polozov Wayne Zeller Hua Cao Rama K. Mishra Alex S. Kiselyov Jose Ramirez Guðrún Halldorsdottir Þorkell Andrésson Mark E. Gurney Jasbir Singh 《Bioorganic & medicinal chemistry letters》2009,19(23):6797-6800
We have developed a pharmacophore model for the EP3 receptor antagonists based on its endogenous ligand PGE2. This ligand-based design yielded a series of novel peri-substituted [4.3.0] bicyclic aromatics featuring 1-alklyaryl 7-heterocyclic sulfonamide substituents. The synthesized molecules are potent antagonists of human EP3 receptor in vitro and show inhibition of rat platelets aggregation. Optimized derivatives display high selectivity over IP, FP, and other EP receptor panels. 相似文献
11.
Kambe T Maruyama T Nakai Y Yoshida H Oida H Maruyama T Abe N Nishiura A Nakai H Toda M 《Bioorganic & medicinal chemistry》2012,20(7):2235-2251
To identify potent EP2/EP4 dual agonists with excellent subtype selectivity, a series of γ-lactam prostaglandin E analogs bearing a 16-phenyl ω-chain were synthesized and evaluated. Structural hybridization of 1 and 2, followed by more detailed chemical modification of the benzoic acid moiety, led us to the discovery of a 2-mercaptothiazole-4-carboxylic acid analog 3 as the optimal compound in the series. An isomer of this compound, the 2-mercaptothiazole-5-carboxylic acid analog 13, showed 34-fold and 13-fold less potent EP2 and EP4 receptor affinities, respectively. Structure activity relationship data from an in vitro mouse receptor binding assay are presented. Continued evaluation in an in vivo rat model of another 2-mercaptothiazole-4-carboxylic acid analog 17, optimized for sustained compound release from PLGA microspheres, demonstrated its effectiveness in a rat bone fracture-healing model following topical administration. 相似文献
12.
Urbahns K Härter M Albers M Schmidt D Stelte-Ludwig B Brüggemeier U Vaupel A Keldenich J Lustig K Tsujishita H Gerdes C 《Bioorganic & medicinal chemistry letters》2007,17(22):6151-6154
Vitronectin receptor (alpha(V)beta(3)) antagonists have been implicated as a possible new treatment of restenosis following balloon angioplasty. In this work we investigate a series of novel arginine mimetic scaffolds leading to new insight of the alpha(V)beta(3)/ligand interaction. Squaric acid amide 10 is a subnanomolar alpha(V)beta(3) antagonist with improved potency on human smooth muscle cell migration. 相似文献
13.
Burch JD Belley M Fortin R Deschênes D Girard M Colucci J Farand J Therien AG Mathieu MC Denis D Vigneault E Lévesque JF Gagné S Wrona M Xu D Clark P Rowland S Han Y 《Bioorganic & medicinal chemistry letters》2008,18(6):2048-2054
A new series of EP(4) antagonists based on a quinoline acylsulfonamide scaffold have been identified as part of our on-going efforts to develop treatments for chronic inflammation. These compounds show subnanomolar intrinsic binding potency towards the EP(4) receptor, and excellent selectivity towards other prostanoid receptors. Acceptable pharmacokinetic profiles have also been demonstrated across a series of preclinical species. 相似文献
14.
Pontillo J Marinkovic D Tran JA Arellano M Fleck BA Wen J Tucci FC Nelson J Saunders J Foster AC Chen C 《Bioorganic & medicinal chemistry letters》2005,15(20):4615-4618
Piperazinebenzylamines bearing a small N-(1-methoxy-2-propyl) side chain were found to be potent and selective antagonists of the human melanocortin-4 (MC4) receptor. Compound 7b, having K(i) values of 6.9 and 2800 nM at the human MC4 and MC3 receptors, respectively, has moderate oral bioavailability in mice, which is improved relative to the arylethyl analogues. 相似文献
15.
《Bioorganic & medicinal chemistry》2016,24(6):1231-1240
A series of 2-sulfonamidopyridine C-region derivatives of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamide were investigated as hTRPV1 ligands. Systematic modification on the 2-sulfonamido group provided highly potent TRPV1 antagonists. The N-benzyl phenylsulfonamide derivatives 12 and 23 in particular showed higher affinities than that of lead compound 1. Compound 12 exhibited strong analgesic activity in the formalin pain model. Docking analysis of its chiral S-form 12S in our hTRPV1 homology model indicated that its high affinity might arise from additional hydrophobic interactions not present in lead compound 1S. 相似文献
16.
Masakazu Atobe Kenji Naganuma Masashi Kawanishi Akifumi Morimoto Ken-ichi Kasahara Shigeki Ohashi Hiroko Suzuki Takahiko Hayashi Shiro Miyoshi 《Bioorganic & medicinal chemistry letters》2013,23(24):6569-6576
We describe a medicinal chemistry approach for generating a series of 2-(1H-pyrazol-1-yl)thiazoles as EP1 receptor antagonists. To improve the physicochemical properties of compound 1, we investigated its structure–activity relationships (SAR). Optimization of this lead compound provided small compound 25 which exhibited the best EP1 receptor antagonist activity and a good SAR profile. 相似文献
17.
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
18.
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
19.
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
20.
Ng RA Guan J Alford VC Lanter JC Allan GF Sbriscia T Lundeen SG Sui Z 《Bioorganic & medicinal chemistry letters》2007,17(4):955-958
The synthesis and in vivo SAR of N-benzyl, N-aceto, and N-ethylene ether derivatives of 2-(2,2,2-trifluoroethyl)-5,6-dichloro-benzimidazole as novel androgen receptor antagonists are described. SAR studies led to the discovery of 4-bromo-benzyl benzimidazole 17 as a more potent androgen receptor antagonist in the rat prostate (ID(50)=0.13mg/day), compared with bicalutamide (ID(50)=0.23mg/day). 相似文献