Discovery of biaryl anthranilides as full agonists for the high affinity niacin receptor.
Biaryl anthranilides are reported as potent and selective full agonists for the high affinity niacin receptor GPR109A. The SAR presented outlines approaches to reduce serum shift and both CYPCYP2C8 and CYP2C9 liabilities, while improving PK and maintaining excellent receptor activity. Compound 2i exhibited good in vivo antilipolytic efficacy while providing a significantly improved therapeutic index over vasodilation (flushing) with respect to niacin in the mouse model.
Shen
Hong C
HC
Merck Research Laboratories, Merck & Co., Inc., Rahway, New Jersey 07065-0900, USA. hong_shen@merck.com
Ding
Fa-Xiang
FX
Luell
Silvi
S
Forrest
Michael J
MJ
Carballo-Jane
Ester
E
Wu
Kenneth K
KK
Wu
Tsuei-Ju
TJ
Cheng
Kang
K
Wilsie
Larissa C
LC
Krsmanovic
Mihajlo L
ML
Taggart
Andrew K
AK
Ren
Ning
N
Cai
Tian-Quan
TQ
Deng
Qiaolin
Q
Chen
Qing
Q
Wang
Junying
J
Wolff
Michael S
MS
Tong
Xinchun
X
Holt
Tom G
TG
Waters
M Gerard
MG
Hammond
Milton L
ML
Tata
James R
JR
Colletti
Steven L
SL
D000577:Amides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D011869:Radioligand Assay; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D011978:Receptors, Nicotinic; D013329:Structure-Activity Relationship; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
D000577:Amides; C530636:HCAR2 protein, human; C473653:HCAR3 protein, human; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D062367:ortho-Aminobenzoates; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8