title: Discovery and optimization of novel purines as potent and selective CB2 agonists.
abstract: A focused screening strategy identified thienopyrimidine 1 as a hCB2 cannabinoid receptor agonist with moderate selectivity over the hCB1 receptor. This initial hit suffered from poor in vitro metabolic stability and high in vivo clearance. Structure-activity relationships describe the optimization and modification to a less lipophilic purine core. Examples from this novel series were found to be highly potent and fully efficacious agonists of the human CB2 receptor with excellent selectivity against CB1. Compound 10 possesses good biopharmaceutical properties, is highly water soluble and demonstrates robust oral activity in rodent models of joint pain.
authors: Discovery Chemistry, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. hollinshead_sean_p@lilly.com
authors: Sean P
authors: SP
authors: Hollinshead
authors: Peter C
authors: PC
authors: Astles
authors: Mark G
authors: MG
authors: Chambers
authors: Michael P
authors: MP
authors: Johnson
authors: John
authors: J
authors: Palmer
authors: Michael W
authors: MW
authors: Tidwell
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical; D005663:Furans / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006207:Half-Life; D006801:Humans; D010146:Pain / Q000188:drug therapy; D011687:Purines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D005663:Furans; D011687:Purines; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2