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G-protein coupled receptor (GPCR) GPR109a is a moleculartarget for nicotinic acid and is expressed in adipocytes, spleen,and immune cells. Nicotinic acid has long been used for the treatmentof dyslipidemia due to its capacity to positively affect serum lipidsto a greater extent than other currently marketed drugs. We reporta series of tricyclic pyrazole carboxylic acids that are potent andselective agonists of GPR109a. Compound R,R-19a(MK-1903) was advanced through preclinicalstudies, was well tolerated, and presented no apparent safety concerns.Compound R,R-19awasadvanced into a phase 1 clinical trial and produced a robust decreasein plasma free fatty acids. On the basis of these results, R,R-19awas evaluated in aphase 2 study in humans. Because R,R-19aproduced only a weak effect on serum lipids ascompared with niacin, we conclude that the beneficial effects of niacinare most likely the result of an undefined GPR109a independent pathway. [ABSTRACT FROM AUTHOR]

Abstract: Tricyclic pyrazole tetrazoles which are potent partial agonists of the high affinity niacin receptor, GPR109a, have been discovered and optimized. One of these compounds has proven to be effective at lowering free fatty acids in vitro and in vivo. [Copyright &y& Elsevier]

Abstract: A strategy for lead identification of new agonists of GPR109a, starting from known compounds shown to activate the receptor, is described. Early compound triage led to the formulation of a binding hypothesis and eventually to our focus on a series of pyrazole acid derivatives. Further elaboration of these compounds provided a series of 5,5-fused pyrazoles to be used as lead compounds for further optimization. [Copyright &y& Elsevier]