Identification and hit-to-lead optimization of a novel class of CB1 antagonists.
The discovery, synthesis and preliminary structure-activity relationships (SARs) of a novel class of CB1 antagonists is described. Initial optimization of benzimidazole-based screening hit 4 led to the identification of 'inverted' indole-based lead compound 18c with improved properties versus compound 4 including reduced AlogP, improved microsomal stability and improved aqueous solubility. Compound 18c demonstrates in vivo CB1 antagonist efficacy (CB1 agonist induced hypothermia model) and is orally bioavailable in rat.
Letourneau
Jeffrey J
JJ
Ligand Pharmaceuticals, Inc., 3000 Eastpark Boulevard, Cranbury, NJ 08512, USA. jletourneau@ligand.com
Jokiel
Patrick
P
Olson
John
J
Riviello
Christopher M
CM
Ho
Koc-Kan
KK
McAleer
Lihong
L
Yang
Jingchun
J
Swanson
Robert N
RN
Baker
James
J
Cowley
Phillip
P
Edwards
Darren
D
Ward
Nick
N
Ohlmeyer
Michael H J
MH
Webb
Maria L
ML
D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007035:Hypothermia / Q000139:chemically induced / Q000188:drug therapy; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012995:Solubility; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D007211:Indoles; D043884:Receptor, Cannabinoid, CB1; C030374:indole; C031000:benzimidazole