title: The SAR development of substituted purine derivatives as selective CB2 agonists for the treatment of chronic pain.
abstract: Osteoarthritis (OA) and the associated joint pain are highly prevalent and a leading cause of disability. We have previously reported the identification of a series of purines as selective CB2 agonists and the identification of compound 1 as a clinical candidate for the treatment of joint pain. In this article we describe the further SAR development of the purine scaffold leading to the discovery of compound 6 as a potent, CNS penetrating CB2 agonist with high selectivity for CB2 over CB1 and oral efficacy in animal models of chronic OA pain.
authors.affiliation: Discovery Chemistry, Erl Wood Manor, Lilly Research Laboratories, A Division of Eli Lilly and Company, Sunningdale Road, Windlesham, Surrey GU20 6PH, UK. Electronic address: guidetti_rossella_rg@lilly.com.
authors.forename: Rossella
authors.initials: R
authors.lastname: Guidetti
authors.affiliation: Discovery Chemistry, Erl Wood Manor, Lilly Research Laboratories, A Division of Eli Lilly and Company, Sunningdale Road, Windlesham, Surrey GU20 6PH, UK.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Astles
authors.affiliation: Discovery Chemistry, Erl Wood Manor, Lilly Research Laboratories, A Division of Eli Lilly and Company, Sunningdale Road, Windlesham, Surrey GU20 6PH, UK.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Sanderson
authors.affiliation: Discovery Chemistry, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Hollinshead
authors.affiliation: Neuroscience Discovery, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Johnson
authors.affiliation: Musculoskeletal Research, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Chambers
mesh_terms: D000818:Animals; D063386:Cannabinoid Receptor Agonists / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D059350:Chronic Pain / Q000188:drug therapy*; D004195:Disease Models, Animal; D004285:Dogs; D006207:Half-Life; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D010003:Osteoarthritis / Q000188:drug therapy; D010879:Piperazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; 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: D063386:Cannabinoid Receptor Agonists; D010879:Piperazines; D011687:Purines; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2
keywords: CB1 selective; CB2 agonist; Osteoarthritis; Pain; Purine