gw-842166x and Inflammation

We describe herein the medicinal chemistry approach which led to the discovery of a novel pyridine-3-carboxamide series of CB(2) receptor agonists. The SAR of this new template was evaluated and culminated in the identification of analogue 14a which demonstrated efficacy in an in vivo model of inflammatory pain.

Topics: Amides; Analgesia; Analgesics; Animals; Disease Models, Animal; Drug Discovery; Inflammation; Pain; Pyridines; Receptor, Cannabinoid, CB2; Structure-Activity Relationship

Identification and optimization of two classes of CB2 selective agonists are described. A representative from each class is profiled in a murine model of inflammation and each shows similar efficacy to prednisolone upon oral dosing.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Cell Line; Chemistry, Pharmaceutical; Drug Design; Humans; Inflammation; Mice; Models, Chemical; Molecular Structure; Morpholines; Receptor, Cannabinoid, CB2; Stereoisomerism

Selective CB2 receptor agonists are promising potential therapeutic agents for the treatment of inflammatory and neuropathic pain. A focused screen identified a pyrimidine ester as a partial agonist at the CB2 receptor with micromolar potency. Subsequent lead optimization identified 35, GW842166X, as the optimal compound in the series. 35 has an oral ED50 of 0.1 mg/kg in the rat FCA model of inflammatory pain and was selected as a clinical candidate for this indication.

Topics: Analgesics; Animals; Biological Availability; Half-Life; Humans; Inflammation; Pain; Pyrans; Pyrimidines; Rats; Receptor, Cannabinoid, CB2; Structure-Activity Relationship