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.
Copyright © 2014 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Cannabinoid Receptor Agonists / chemistry
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Cannabinoid Receptor Agonists / pharmacokinetics
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Cannabinoid Receptor Agonists / therapeutic use*
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Chronic Pain / drug therapy*
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Disease Models, Animal
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Dogs
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Half-Life
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Humans
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Microsomes, Liver / metabolism
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Osteoarthritis / drug therapy
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Piperazines / chemistry*
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Piperazines / pharmacokinetics
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Piperazines / therapeutic use
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Purines / chemistry*
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Purines / pharmacokinetics
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Purines / therapeutic use
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Rats
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Receptor, Cannabinoid, CB1 / agonists
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Receptor, Cannabinoid, CB1 / metabolism
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Receptor, Cannabinoid, CB2 / agonists*
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Receptor, Cannabinoid, CB2 / metabolism
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Structure-Activity Relationship
Substances
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Cannabinoid Receptor Agonists
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Piperazines
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Purines
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Receptor, Cannabinoid, CB1
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Receptor, Cannabinoid, CB2