title: Discovery of a vorapaxar analog with increased aqueous solubility.
abstract: An analog of the thrombin receptor antagonist vorapaxar (SCH 530348) with increased aqueous solubility, compound 9c (SCH 602539), was discovered through incorporation of polar substituents on the pyridine ring of the himbacine-derived lead series. This analog retained the excellent potency, pharmacokinetic and safety properties of vorapaxar while increasing the aqueous solubility by 20-fold. Also presented are in vivo evaluations of this compound in a cynomolgus monkey platelet aggregation assay and in a Folts model of thrombosis in anesthetized monkeys.
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. yan.xia@merck.com
authors.forename: Yan
authors.initials: Y
authors.lastname: Xia
authors.forename: Samuel
authors.initials: S
authors.lastname: Chackalamannil
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: Yuguang
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Hu
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Root
authors.forename: Jesse
authors.initials: J
authors.lastname: Wong
authors.forename: Jianshe
authors.initials: J
authors.lastname: Kong
authors.forename: Ho-Sam
authors.initials: HS
authors.lastname: Ahn
authors.forename: George
authors.initials: G
authors.lastname: Boykow
authors.forename: Yunsheng
authors.initials: Y
authors.lastname: Hsieh
authors.forename: Stan
authors.initials: S
authors.lastname: Kurowski
authors.forename: Madhu
authors.initials: M
authors.lastname: Chintala
mesh_terms: D000818:Animals; D055808:Drug Discovery; D006801:Humans; D020128:Inhibitory Concentration 50; D007783:Lactones / Q000737:chemistry* / Q000494:pharmacology; D008252:Macaca fascicularis; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors; D012995:Solubility; D014867:Water / Q000737:chemistry*
chemical_list: D007783:Lactones; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D018179:Receptors, Thrombin; D014867:Water; C530299:vorapaxar