title: (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.
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.
authors.affiliation: Department of Medicinal Chemistry, Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, California 92121, USA. pdboatman@yahoo.com
authors.forename: P Douglas
authors.initials: PD
authors.lastname: Boatman
authors.forename: Brett
authors.initials: B
authors.lastname: Lauring
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Schrader
authors.forename: Michelle
authors.initials: M
authors.lastname: Kasem
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Johnson
authors.forename: Philip
authors.initials: P
authors.lastname: Skinner
authors.forename: Jae-Kyu
authors.initials: JK
authors.lastname: Jung
authors.forename: Jerry
authors.initials: J
authors.lastname: Xu
authors.forename: Martin C
authors.initials: MC
authors.lastname: Cherrier
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Webb
authors.forename: Graeme
authors.initials: G
authors.lastname: Semple
authors.forename: Carleton R
authors.initials: CR
authors.lastname: Sage
authors.forename: Jens
authors.initials: J
authors.lastname: Knudsen
authors.forename: Ruoping
authors.initials: R
authors.lastname: Chen
authors.forename: Wen-Lin
authors.initials: WL
authors.lastname: Luo
authors.forename: Luzelena
authors.initials: L
authors.lastname: Caro
authors.forename: Josee
authors.initials: J
authors.lastname: Cote
authors.forename: Eseng
authors.initials: E
authors.lastname: Lai
authors.forename: John
authors.initials: J
authors.lastname: Wagner
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Taggart
authors.forename: Ester
authors.initials: E
authors.lastname: Carballo-Jane
authors.forename: Milton
authors.initials: M
authors.lastname: Hammond
authors.forename: Steven L
authors.initials: SL
authors.lastname: Colletti
authors.forename: James R
authors.initials: JR
authors.lastname: Tata
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Connolly
authors.forename: M Gerard
authors.initials: MG
authors.lastname: Waters
authors.forename: Jeremy G
authors.initials: JG
authors.lastname: Richman
mesh_terms: D000818:Animals; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D006801:Humans; D000960:Hypolipidemic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D009525:Niacin / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000187:drug effects; D013237:Stereoisomerism; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: C573553:1a,3,5,5a-tetrahydro-1H-2,3-diazacyclopropa(a)pentalene-4-carboxylic acid; D005230:Fatty Acids, Nonesterified; C530636:HCAR2 protein, human; D000960:Hypolipidemic Agents; D011720:Pyrazoles; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D014665:Vasodilator Agents; D009525:Niacin