Agonist lead identification for the high affinity niacin receptor GPR109a.
A strategy for lead identification of new agonists of GPR109a, starting from known compounds shown to activate the receptor, is described. Early compound triage led to the formulation of a binding hypothesis and eventually to our focus on a series of pyrazole acid derivatives. Further elaboration of these compounds provided a series of 5,5-fused pyrazoles to be used as lead compounds for further optimization.
Gharbaoui
Tawfik
T
Department of Medicinal Chemistry, Arena Pharmaceuticals, San Diego, CA 92121, USA.
Skinner
Philip J
PJ
Shin
Young-Jun
YJ
Averbuj
Claudia
C
Jung
Jae-Kyu
JK
Johnson
Benjamin R
BR
Duong
Tracy
T
Decaire
Marc
M
Uy
Jane
J
Cherrier
Martin C
MC
Webb
Peter J
PJ
Tamura
Susan Y
SY
Zou
Ning
N
Rodriguez
Nathalie
N
Boatman
P Douglas
PD
Sage
Carleton R
CR
Lindstrom
Andrew
A
Xu
Jerry
J
Schrader
Thomas O
TO
Smith
Brian M
BM
Chen
Ruoping
R
Richman
Jeremy G
JG
Connolly
Daniel T
DT
Colletti
Steven L
SL
Tata
James R
JR
Semple
Graeme
G
D000147:Acids, Heterocyclic / Q000737:chemistry*; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D000242:Cyclic AMP / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D009525:Niacin / Q000737:chemistry; D011720:Pyrazoles / Q000737:chemistry; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry*; D011978:Receptors, Nicotinic / Q000737:chemistry*; D013154:Spleen / Q000378:metabolism
D000147:Acids, Heterocyclic; C530636:HCAR2 protein, human; C473653:HCAR3 protein, human; D011720:Pyrazoles; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D009525:Niacin; D000242:Cyclic AMP