Tetrahydro anthranilic acid as a surrogate for anthranilic acid: application to the discovery of potent niacin receptor agonists.
The design, synthesis, and biological activity of a series of cycloalkene acid-based niacin receptor agonists are described. This led to the discovery that tetrahydro anthranilic acid is an excellent surrogate for anthranilic acid. Several compounds were identified that were potent against the niacin receptor, had enhanced cytochrome P450 selectivity against subtypes CYP2C8 and CYP2C9, and improved oral exposure in mice.
Raghavan
Subharekha
S
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. subha_raghavan@merck.com
Tria
G Scott
GS
Shen
Hong C
HC
Ding
Fa-Xiang
FX
Taggart
Andrew K
AK
Ren
Ning
N
Wilsie
Larrisa C
LC
Krsmanovic
Mihajlo L
ML
Holt
Tom G
TG
Wolff
Michael S
MS
Waters
M Gerard
MG
Hammond
Milton L
ML
Tata
James R
JR
Colletti
Steven L
SL
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000187:drug effects; D053138:Cyclohexenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D051379:Mice; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
D053138:Cyclohexenes; D003517:Cyclopentanes; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D062367:ortho-Aminobenzoates; C031385:anthranilic acid; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8