Discovery of novel tricyclic full agonists for the G-protein-coupled niacin receptor 109A with minimized flushing in rats.
Tricyclic analogues were rationally designed as the high affinity niacin receptor G-protein-coupled receptor 109A (GPR109A) agonists by overlapping three lead structures. Various tricyclic anthranilide and cycloalkene carboxylic acid full agonists were discovered with excellent in vitro activity. Compound 2g displayed a good therapeutic index regarding free fatty acids (FFA) reduction and vasodilation effects in rats, with very weak cytochrome P450 2C8 (CYP2C8) and cytochrome P450 2C9 (CYP2C9) inhibition, and a good mouse pharmacokinetics (PK) profile.
Shen
Hong C
HC
Departments of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., Rahway, New Jersey 07065-0900, USA. hong_shen@merck.com
Ding
Fa-Xiang
FX
Deng
Qiaolin
Q
Wilsie
Larissa C
LC
Krsmanovic
Mihajlo L
ML
Taggart
Andrew K
AK
Carballo-Jane
Ester
E
Ren
Ning
N
Cai
Tian-Quan
TQ
Wu
Tsuei-Ju
TJ
Wu
Kenneth K
KK
Cheng
Kang
K
Chen
Qing
Q
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
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003516:Cycloparaffins / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D004423:Ear / Q000098:blood supply; D005483:Flushing / Q000139:chemically induced*; D006575:Heterocyclic Compounds, 3-Ring / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D000960:Hypolipidemic Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D008066:Lipolysis; D008297:Male; D051379:Mice; D009525:Niacin / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D011978:Receptors, Nicotinic; D013329:Structure-Activity Relationship; D014664:Vasodilation / Q000187:drug effects; D062367:ortho-Aminobenzoates / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology
D003516:Cycloparaffins; C530636:HCAR2 protein, human; C473653:HCAR3 protein, human; D006575:Heterocyclic Compounds, 3-Ring; D000960:Hypolipidemic Agents; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D062367:ortho-Aminobenzoates; D009525:Niacin