title: Bioisosteric replacement of the pyrazole 5-aryl moiety of N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A). A novel series of alkynylthiophenes as potent and selective cannabinoid-1 receptor antagonists.
abstract: Replacing the conventional pyrazole 5-aryl substituent of 1 (SR141716A) with the 2-thienyl moiety appended with an appropriate alkynyl unit, a novel class of 5-(5-alkynyl-2-thienyl)pyrazole derivatives, behaving as highly potent CB1 receptor antagonists with good CB1/2 selectivity, was discovered, many of which, as typified by compound 18, showed significant weight reduction in diet-induced obese mouse model, thus pharmacologically validating that the bioisosteric replacement described above is viable. Also encouraging was the finding that a subtle structural modification of the newly developed series could result in a distinct difference in the intrinsic property, as demonstrated by compounds 12 (NA) and its methylated structural isomers 15 (PA) and 18 (IA). Moreover, current structure-activity relationship studies revealed that around the pyrazole 5-position of 1, a deep and flat crevice surrounded by a sequence of hydrophobic/aromatic residues as indicated by the CB1-receptor homology model might exist in the binding site.
authors: Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors: Shi-Liang
authors: SL
authors: Tseng
authors: Ming-Shiu
authors: MS
authors: Hung
authors: Chun-Ping
authors: CP
authors: Chang
authors: Jen-Shin
authors: JS
authors: Song
authors: Chia-Liang
authors: CL
authors: Tai
authors: Hua-Hao
authors: HH
authors: Chiu
authors: Wan-Ping
authors: WP
authors: Hsieh
authors: Yinchiu
authors: Y
authors: Lin
authors: Wan-Ling
authors: WL
authors: Chung
authors: Chun-Wei
authors: CW
authors: Kuo
authors: Chien-Huang
authors: CH
authors: Wu
authors: Cheng-Ming
authors: CM
authors: Chu
authors: Yen-Shih
authors: YS
authors: Tung
authors: Yu-Sheng
authors: YS
authors: Chao
authors: Kak-Shan
authors: KS
authors: Shia
mesh_terms: D000818:Animals; D001665:Binding Sites; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008820:Mice, Obese; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D000077285:Rimonabant; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D015431:Weight Loss / Q000187:drug effects*
chemical_list: D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D013876:Thiophenes; C031280:pyrazole; D000077285:Rimonabant