Document Detail


(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.
MedLine Citation:
PMID:  22435740     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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. Based on these results, R,R-19a was evaluated in a Phase 2 study in humans. Since 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.
Authors:
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 Cabrallo-Jane; Milton Hammond; Steven L Colletti; James R Tata; Daniel T Connolly; M Gerard Waters; Jeremy G Richman
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-3-21
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  -     ISSN:  1520-4804     ISO Abbreviation:  -     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-3-22     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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