title: Tetrahydro anthranilic acid as a surrogate for anthranilic acid: application to the discovery of potent niacin receptor agonists.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. subha_raghavan@merck.com
authors.forename: Subharekha
authors.initials: S
authors.lastname: Raghavan
authors.forename: G Scott
authors.initials: GS
authors.lastname: Tria
authors.forename: Hong C
authors.initials: HC
authors.lastname: Shen
authors.forename: Fa-Xiang
authors.initials: FX
authors.lastname: Ding
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Taggart
authors.forename: Ning
authors.initials: N
authors.lastname: Ren
authors.forename: Larrisa C
authors.initials: LC
authors.lastname: Wilsie
authors.forename: Mihajlo L
authors.initials: ML
authors.lastname: Krsmanovic
authors.forename: Tom G
authors.initials: TG
authors.lastname: Holt
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wolff
authors.forename: M Gerard
authors.initials: MG
authors.lastname: Waters
authors.forename: Milton L
authors.initials: ML
authors.lastname: Hammond
authors.forename: James R
authors.initials: JR
authors.lastname: Tata
authors.forename: Steven L
authors.initials: SL
authors.lastname: Colletti
mesh_terms: 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*
chemical_list: 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