hu-210 and Pain

In our ongoing program aimed at deeply investigating the endocannabinoid system (ES), a set of new alkyl-resorcinol derivatives was prepared focusing on the nature and the importance of the carboxamide functionality. Binding studies on CB1 and CB2 receptors, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) showed that some of the newly developed compounds behaved as very potent cannabinoid receptor ligands (Ki in the nanomolar range) while, however, none of them was able to inhibit MAGL and/or FAAH. Derivative 11 was a potent CB1 and CB2 ligand, with Ki values similar to WIN 55,212, exhibiting a CB1 and CB2 agonist profile in vitro. In the formalin test of peripheral acute and inflammatory pain in mice, this compound showed a weak and delayed antinociceptive effect against the second phase of the nocifensive response, exhibiting, interestingly, a quite potent transient receptor potential ankyrin type-1 (TRPA1) channel agonist activity. Moreover, derivative 14, characterized by lower affinity but higher CB2 selectivity than 11, proved to behave as a weak CB2 competitive inverse agonist.

Topics: Analgesics; Animals; Calcium Channels; Cell Survival; Cells, Cultured; CHO Cells; Cricetulus; Dose-Response Relationship, Drug; Humans; Ligands; Male; Mice; Molecular Structure; Nerve Tissue Proteins; NIH 3T3 Cells; Nociception; Pain; Pain Measurement; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Resorcinols; Structure-Activity Relationship; Transient Receptor Potential Channels; TRPA1 Cation Channel

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

We report the synthesis and SAR of a series of novel azaindole CB(2) agonists. 6-Azaindole 18 showed activity in an acute pain model but was inactive in a chronic model. 18 is a Pgp substrate with low brain penetration. The template was redesigned, and the resulting 5-azaindole 36 was a potent CB(2) agonist with high CNS penetration. This compound was efficacious in the acute model and the chronic joint pain model.

Topics: Aminopyridines; Animals; Aza Compounds; Brain; Cell Line; CHO Cells; Chronic Disease; Cricetinae; Cricetulus; Drug Discovery; Humans; Indoles; Morpholines; Pain; Rats; Receptor, Cannabinoid, CB2; Structure-Activity Relationship

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