Discovery of orally bioavailable and novel urea agonists of the high affinity niacin receptor GPR109A.
A urea class of high affinity niacin receptor agonists was discovered. Compound 1a displayed good PK, better in vivo efficacy in reducing FFA in mouse than niacin, and no vasodilation in a mouse model. Compound 1q demonstrated equal affinity to GPR109A as niacin.
Shen
Hong C
HC
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA. hong_shen@merck.com
Szymonifka
Michael J
MJ
Kharbanda
Divya
D
Deng
Qiaolin
Q
Carballo-Jane
Ester
E
Wu
Kenneth K
KK
Wu
Tsuei-Ju
TJ
Cheng
Kang
K
Ren
Ning
N
Cai
Tian-Quan
TQ
Taggart
Andrew K
AK
Wang
Junying
J
Tong
Xinchun
X
Waters
M Gerard
MG
Hammond
Milton L
ML
Tata
James R
JR
Colletti
Steven L
SL
D000818:Animals; D020650:Combinatorial Chemistry Techniques; D006801:Humans; D008297:Male; D051379:Mice; D023421:Models, Animal; D015394:Molecular Structure; D009525:Niacin / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D011978:Receptors, Nicotinic; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D014664:Vasodilation / Q000187:drug effects
C473652:Hcar2 protein, mouse; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D009525:Niacin; D014508:Urea