title: Identification and hit-to-lead optimization of a novel class of CB1 antagonists.
abstract: 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.
authors: Ligand Pharmaceuticals, Inc., 3000 Eastpark Boulevard, Cranbury, NJ 08512, USA. jletourneau@ligand.com
authors: Jeffrey J
authors: JJ
authors: Letourneau
authors: Patrick
authors: P
authors: Jokiel
authors: John
authors: J
authors: Olson
authors: Christopher M
authors: CM
authors: Riviello
authors: Koc-Kan
authors: KK
authors: Ho
authors: Lihong
authors: L
authors: McAleer
authors: Jingchun
authors: J
authors: Yang
authors: Robert N
authors: RN
authors: Swanson
authors: James
authors: J
authors: Baker
authors: Phillip
authors: P
authors: Cowley
authors: Darren
authors: D
authors: Edwards
authors: Nick
authors: N
authors: Ward
authors: Michael H J
authors: MH
authors: Ohlmeyer
authors: Maria L
authors: ML
authors: Webb
mesh_terms: 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
chemical_list: D001562:Benzimidazoles; D007211:Indoles; D043884:Receptor, Cannabinoid, CB1; C030374:indole; C031000:benzimidazole