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

Rossella Guidetti; Peter C Astles; Adam J Sanderson; Sean P Hollinshead; Michael P Johnson; Mark G Chambers

doi:10.1016/j.bmcl.2014.11.006

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. Epub 2014 Nov 7.

Authors

Rossella Guidetti¹, Peter C Astles², Adam J Sanderson², Sean P Hollinshead³, Michael P Johnson⁴, Mark G Chambers⁵

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.

MeSH terms

Animals
Cannabinoid Receptor Agonists / chemistry
Cannabinoid Receptor Agonists / pharmacokinetics
Cannabinoid Receptor Agonists / therapeutic use*
Chronic Pain / drug therapy*
Disease Models, Animal
Dogs
Half-Life
Humans
Microsomes, Liver / metabolism
Osteoarthritis / drug therapy
Piperazines / chemistry*
Piperazines / pharmacokinetics
Piperazines / therapeutic use
Purines / chemistry*
Purines / pharmacokinetics
Purines / therapeutic use
Rats
Receptor, Cannabinoid, CB1 / agonists
Receptor, Cannabinoid, CB1 / metabolism
Receptor, Cannabinoid, CB2 / agonists*
Receptor, Cannabinoid, CB2 / metabolism
Structure-Activity Relationship

Substances

Cannabinoid Receptor Agonists
Piperazines
Purines
Receptor, Cannabinoid, CB1
Receptor, Cannabinoid, CB2