The G protein-coupled receptor (GPCR) GPR35 is expressed throughout the body, especially in gastrointestinal tissues and on immune cells. GPR35 agonists have potential for the treatment of inflammatory conditions, including inflammatory bowel disease and neuropathic pain, and may also be beneficial for treating hypertension and heart failure. Several classes of potent agonists for the human GPR35 have been described, including 8-benzamidochromen-4-one-2-carboxylic acid derivatives developed by our group. However, large species differences are typically observed, and the compounds’ potency is generally much lower at the rat and especially at the mouse as compared to the human receptor. This hampers target validation and exploration of the GPR35 agonists in animal models. The present study was aimed at the development of novel GPR35 agonists with high potency at human, rat, and mouse receptors, combined with high selectivity versus related GPCRs. Chromen-4-one-2-carboxylic acid derivatives (1) and related 1,7-phenanthroline-2,8-dicarboxylic acid derivatives (2) were synthesized and characterized in GPR35-dependent beta-arrestin recruitment assays. Careful analysis of structure-activity relationships served as a basis for optimization to obtain agonists with similar, nanomolar potencies in all three targeted species. The best compounds of the present series showed EC50 values in the low nanomolar range. All of the compounds were found to be highly selective versus closely related GPCRs including GPR55, determined in the same test system.

Development of potent GPR35 agonists with activity at human and rodent receptors

2019 Spring National Meeting

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