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: [email protected].
  • 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.