(1aR,5aR)1a,3,5,5a-Tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid (MK-1903): A Potent GPR109a Agonist that Lowers Free Fatty Acids in Humans

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• 作者：P. Douglas Boatman ; Brett Lauring ; Thomas O. Schrader ; Michelle Kasem ; Benjamin R. Johnson ; Philip Skinner ; Jae-Kyu Jung ; Jerry Xu ; Martin C. Cherrier ; Peter J. Webb ; Graeme Semple ; Carleton R. Sage ; Jens Knudsen ; Ruoping Chen ; Wen-Lin Luo ; Luzelena Caro ; Josee Cote ; Eseng Lai ; John Wagner ; Andrew K. Taggart ; Ester Carballo-Jane ; Milton Hammond ; Steven L. Colletti ; James R. Tata ; Daniel T. Connolly ; M. Gerard Waters ; Jeremy G. Richman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：April 26, 2012
• 年：2012
• 卷：55
• 期：8
• 页码：3644-3666
• 全文大小：723K
• 年卷期：v.55,no.8(April 26, 2012)
• ISSN：1520-4804

文摘

G-protein coupled receptor (GPCR) GPR109a is a molecular target for nicotinic acid and is expressed in adipocytes, spleen, and immune cells. Nicotinic acid has long been used for the treatment of dyslipidemia due to its capacity to positively affect serum lipids to a greater extent than other currently marketed drugs. We report a series of tricyclic pyrazole carboxylic acids that are potent and selective agonists of GPR109a. Compound R,R-19a (MK-1903) was advanced through preclinical studies, was well tolerated, and presented no apparent safety concerns. Compound R,R-19a was advanced into a phase 1 clinical trial and produced a robust decrease in plasma free fatty acids. On the basis of these results, R,R-19a was evaluated in a phase 2 study in humans. Because R,R-19a produced only a weak effect on serum lipids as compared with niacin, we conclude that the beneficial effects of niacin are most likely the result of an undefined GPR109a independent pathway.