The SAR development of substituted purine derivatives as selective CB2 agonists for the treatment of chronic pain

Bioorg Med Chem Lett. 2014 Dec 15;24(24):5572-5575. doi: 10.1016/j.bmcl.2014.11.006.

Rossella Guidetti ¹, Peter C Astles ², Adam J Sanderson ², Sean P Hollinshead ³, Michael P Johnson ⁴, Mark G Chambers ⁵

Affiliations

1 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.
2 Discovery Chemistry, Erl Wood Manor, Lilly Research Laboratories, A Division of Eli Lilly and Company, Sunningdale Road, Windlesham, Surrey GU20 6PH, UK.
3 Discovery Chemistry, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
4 Neuroscience Discovery, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
5 Musculoskeletal Research, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.

PMID: 25466177 DOI: 10.1016/j.bmcl.2014.11.006

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.

Keywords

CB1 selective; CB2 agonist; Osteoarthritis; Pain; Purine.

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