title: Methylsulfonylpyrazolyl oxadiazoles and thiadiazoles as potent, orally bioavailable cannabinoid-1 receptor antagonists for the treatment of obesity.
abstract: BACKGROUND
  Since the cannabinoid receptor 1 (CB1) antagonist SR141716 (rimonabant) was previously reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target for the treatment of obesity.
  
  
  CONCLUSIONS
  In the present study, biarylpyrazole analogues based on a sulfur-containing pyrazole core coupled with 1,3,4-oxadiazole and 1,3,4-thiadiazole were synthesized and assayed for rat CB1 receptor binding affinity.
  
  
  RESULTS
  The structure-activity relationship studies to optimize pyrazole substituents as well as 1,3,4-oxadiazole or 1,3,4-thiadiazole rings led to four novel CB1 antagonists with IC(50) values of approximately 1 nM for the rat CB1 receptor binding. Among these derivatives, we identified trifluoromethylcyclobutyl analogues 19e and 19l as promising precandidates for the development as anti-obesity agents.
authors.affiliation: Central Research Laboratories, Green Cross Corporation, 303 Bojeong-dong, Giheung-gu, Yongin 446-770, Korea.
authors.forename: Hee Jeong
authors.initials: HJ
authors.lastname: Seo
authors.forename: Min Ju
authors.initials: MJ
authors.lastname: Kim
authors.forename: Kwang-Seop
authors.initials: KS
authors.lastname: Song
authors.forename: Sung-Han
authors.initials: SH
authors.lastname: Lee
authors.forename: Myung Eun
authors.initials: ME
authors.lastname: Jung
authors.forename: Mi-Soon
authors.initials: MS
authors.lastname: Kim
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Park
authors.forename: Jakyung
authors.initials: J
authors.lastname: Yoo
authors.forename: Chong-Hwan
authors.initials: CH
authors.lastname: Chang
authors.forename: Jeongmin
authors.initials: J
authors.lastname: Kim
authors.forename: Jinhwa
authors.initials: J
authors.lastname: Lee
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019440:Anti-Obesity Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001665:Binding Sites; D001682:Biological Availability; D003198:Computer Simulation; D006801:Humans; D051379:Mice; D009765:Obesity / Q000188:drug therapy*; D010069:Oxadiazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011720:Pyrazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: C559397:2-(1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-(methylsulfonyl)-1H-pyrazol-3-yl)-5-(1-(trifluoromethyl)cyclobutyl)-1,3,4-thiadiazole; C559398:2-(5-(4-bromophenyl)-1-(2-chlorophenyl)-4-(methylsulfonyl)-1H-pyrazol-3-yl)-5-(1-(trifluoromethyl)cyclobutyl)-1,3,4-thiadiazole; D019440:Anti-Obesity Agents; D010069:Oxadiazoles; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D013830:Thiadiazoles