Synthesis and SAR of 5,6-diarylpyridines as human CB1 inverse agonists.
Structure-activity relationship studies for two series of 2-benzyloxy-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyridines having either a 3-cyano or 3-carboxamide moiety resulted in the preparation of the 2-(3,4-difluorobenzyloxy)-3-nitrile analog 10d and the 2-(3,4-difluorobenzyloxy)-3-(N-propylcarboxamide) analog 16c, (hCB1 IC(50)=1.3 and 1.7 nM, respectively) as potent and selective hCB1 inverse agonists. Their synthesis and biological activities are described herein.
Meurer
Laura C
LC
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. laura_meurer@merck.com
Finke
Paul E
PE
Mills
Sander G
SG
Walsh
Thomas F
TF
Toupence
Richard B
RB
Debenham
John S
JS
Goulet
Mark T
MT
Wang
Junying
J
Tong
Xinchun
X
Fong
Tung M
TM
Lao
Julie
J
Schaeffer
Marie-Therese
MT
Chen
Jing
J
Shen
Chun-Pyn
CP
Sloan Stribling
D
D
Shearman
Lauren P
LP
Strack
Alison M
AM
Van der Ploeg
Lex H T
LH
D000818:Animals; D001682:Biological Availability; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014162:Transfection
D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1