Niacin (nicotinic acid) has been used for the prevention and treatment of cardiovascular disease for many years. A resurgence of interest in this area since the discovery of a molecular target for niacin (GPR109a) focused on niacin's ability to increase high density lipoprotein-cholesterol (HDL-C) to a greater extent than other currently available drugs.The identification of agonist ligands for HCA2 via a classical SAR approach will be described, leading to the discovery of MK-0354. In vivo, MK-0354 inhibited lipolysis with comparable efficacy to niacin in acute models and showed a markedly improved therapeutic window between plasma FFA reduction and cutaneous flushing across multiple species. We subsequently showed that the two in vivo effects may be separated on the basis of the compound's differential signaling properties in key cell types. The identification of second generation clinical candidates will also be described.

Agonists of the nicotinic acid receptor (HCA<sub>2</sub>, GPR109a,)

243rd National Meeting (2012)

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Agonists of the nicotinic acid receptor (HCA2, GPR109a,)

Agonists of the nicotinic acid receptor (HCA₂, GPR109a,)