Oxadiazole-diarylpyrazole 4-carboxamides as cannabinoid CB1 receptor ligands.
Cannabinoid CB-1 receptors have been the focus of extensive studies since the first clinical results of rimonabant (SR141716) for the treatment of obesity and obesity-related metabolic disorders were reported in 2001. To further evaluate the properties of CB receptors, we have designed and efficiently prepared a series of oxadiazole-diarylpyrazole 4-carboxamides. Six of the new compounds which displayed high in vitro CB1 binding affinities were assayed for binding to CB2 receptor. Noticeably, 5-(4-bromophenyl)-3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-(2,4-dichlorophenyl)-N-phenyl-1H-pyrazole-4-carboxamide (12q) and 5-(4-bromophenyl)-3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-(2,4-dichlorophenyl)-N-(pyridin-2-yl)-1H-pyrazole-4-carboxamide (12r) demonstrated good binding affinity and decent selectivity for CB1 receptor (IC(50) = 1.35 nM, CB2/CB1 = 286 for 12q; IC(50) = 1.46 nM, CB2/CB1 = 256 for 12r).
Lee
Suk Ho
SH
Central Research Laboratories, Green Cross Corporation, 303 Bojeong-Dong, Giheung-Gu, Yongin, Gyeonggi-Do 446-770, Republic of Korea.
Seo
Hee Jeong
HJ
Kim
Min Ju
MJ
Kang
Suk Youn
SY
Song
Kwang-Seop
KS
Lee
Sung-Han
SH
Jung
Myung Eun
ME
Kim
Jeongmin
J
Lee
Jinhwa
J
D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D020128:Inhibitory Concentration 50; D008024:Ligands; D009765:Obesity / Q000188:drug therapy; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection
C541277:5-(4-bromophenyl)-3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-(2,4-dichlorophenyl)-N-(pyridin-2-yl)-1H-pyrazole-4-carboxamide; C541276:5-(4-bromophenyl)-3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-(2,4-dichlorophenyl)-N-phenyl-1H-pyrazole-4-carboxamide; D019440:Anti-Obesity Agents; D008024:Ligands; D010069:Oxadiazoles; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1