3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole (MK-0354): a partial agonist of the nicotinic acid receptor, G-protein coupled receptor 109a, with antilipolytic but no vasodilatory activity in mice.
The discovery and profiling of 3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole (5a, MK-0354), a partial agonist of GPR109a, is described. Compound 5a retained the plasma free fatty acid lowering effects in mice associated with GPR109a agonism, but did not induce vasodilation at the maximum feasible dose. Moreover, preadministration of 5a blocked the flushing effect induced by nicotinic acid but not that induced by PGD2. This profile made 5a a suitable candidate for further study for the treatment of dyslipidemia.
Semple
Graeme
G
Department of Medicinal Chemistry, Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, California 92121, USA. gsemple@arenapharm.com
Skinner
Philip J
PJ
Gharbaoui
Tawfik
T
Shin
Young-Jun
YJ
Jung
Jae-Kyu
JK
Cherrier
Martin C
MC
Webb
Peter J
PJ
Tamura
Susan Y
SY
Boatman
P Douglas
PD
Sage
Carleton R
CR
Schrader
Thomas O
TO
Chen
Ruoping
R
Colletti
Steven L
SL
Tata
James R
JR
Waters
M Gerard
MG
Cheng
Kang
K
Taggart
Andrew K
AK
Cai
Tian-Quan
TQ
Carballo-Jane
Ester
E
Behan
Dominic P
DP
Connolly
Daniel T
DT
Richman
Jeremy G
JG
D017667:Adipocytes / Q000187:drug effects; D000818:Animals; D005230:Fatty Acids, Nonesterified / Q000097:blood; D006801:Humans; D000960:Hypolipidemic Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D008066:Lipolysis / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011720:Pyrazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D011978:Receptors, Nicotinic; D013777:Tetrazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D014664:Vasodilation / Q000187:drug effects
C531233:3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydrocyclopentapyrazole; D005230:Fatty Acids, Nonesterified; C530636:HCAR2 protein, human; C473653:HCAR3 protein, human; D000960:Hypolipidemic Agents; D011720:Pyrazoles; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D013777:Tetrazoles