Fluorinated pyrazole acids are agonists of the high affinity niacin receptor GPR109a.
A series of 5-alkyl pyrazole-3-carboxylic acids were prepared and found to act as potent and selective agonists of the human GPCR, GPR109a, the high affinity nicotinic acid receptor. No activity was observed at the highly homologous low affinity niacin receptor, GPR109b. A further series of 4-fluoro-5-alkyl pyrazole-3-carboxylic acids were shown to display similar potency. One example from the series was shown to have improved properties in vivo compared to niacin.
Skinner
Philip J
PJ
Medicinal Chemistry, Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, CA 92121, USA. pskinner@arenapharm.com
Cherrier
Martin C
MC
Webb
Peter J
PJ
Shin
Young-Jun
YJ
Gharbaoui
Tawfik
T
Lindstrom
Andrew
A
Hong
Vu
V
Tamura
Susan Y
SY
Dang
Huong T
HT
Pride
Cameron C
CC
Chen
Ruoping
R
Richman
Jeremy G
JG
Connolly
Daniel T
DT
Semple
Graeme
G
D000143:Acids / Q000737:chemistry*; D000818:Animals; D005227:Fatty Acids / Q000378:metabolism; D005461:Fluorine / Q000737:chemistry*; D008024:Ligands; D008297:Male; D051379:Mice; D015394:Molecular Structure; D018722:Nicotinic Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism; D013329:Structure-Activity Relationship