2. Academic Validation
  3. (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

(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

  • J Med Chem. 2012 Apr 26;55(8):3644-66. doi: 10.1021/jm2010964.
P Douglas Boatman 1,  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
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, California 92121, USA. pdboatman@yahoo.com
PMID: 22435740 DOI: 10.1021/jm2010964
Abstract

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.

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