Discovery of a vorapaxar analog with increased aqueous solubility.
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.
Xia
Yan
Y
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. yan.xia@merck.com
Chackalamannil
Samuel
S
Greenlee
William J
WJ
Wang
Yuguang
Y
Hu
Zhiyong
Z
Root
Yuriko
Y
Wong
Jesse
J
Kong
Jianshe
J
Ahn
Ho-Sam
HS
Boykow
George
G
Hsieh
Yunsheng
Y
Kurowski
Stan
S
Chintala
Madhu
M
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*
D007783:Lactones; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D018179:Receptors, Thrombin; D014867:Water; C530299:vorapaxar