title: Metabolism-based identification of a potent thrombin receptor antagonist.
abstract: The metabolism of our prototypical thrombin receptor antagonist 1, Ki = 2.7 nM, was studied and three major metabolites (2, 4, and 5) were found. The structures of the metabolites were verified independently by synthesis. Compound 4 was shown to be a potent antagonist of the thrombin receptor with a Ki = 11 nM. Additionally, compound 4 showed a 3-fold improvement in potency with respect to 1 in an agonist-induced ex-vivo platelet aggregation assay in cynomolgus monkeys after oral administration; this activity was sustained with 60% inhibition observed at 24 h post-dose. Compound 4 was highly active in functional assays and showed excellent oral bioavailability in rats and monkeys. Compound 4 showed a superior rat enzyme induction profile relative to compound 1, allowing it to replace compound 1 as a development candidate.
authors.affiliation: Central Nervous System and Cardiovascular Chemical Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
authors.forename: Martin C
authors.initials: MC
authors.lastname: Clasby
authors.forename: Samuel
authors.initials: S
authors.lastname: Chackalamannil
authors.forename: Michael
authors.initials: M
authors.lastname: Czarniecki
authors.forename: Dario
authors.initials: D
authors.lastname: Doller
authors.forename: Keith
authors.initials: K
authors.lastname: Eagen
authors.forename: William
authors.initials: W
authors.lastname: Greenlee
authors.forename: Grace
authors.initials: G
authors.lastname: Kao
authors.forename: Yan
authors.initials: Y
authors.lastname: Lin
authors.forename: Hsingan
authors.initials: H
authors.lastname: Tsai
authors.forename: Yan
authors.initials: Y
authors.lastname: Xia
authors.forename: Ho-Sam
authors.initials: HS
authors.lastname: Ahn
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Agans-Fantuzzi
authors.forename: George
authors.initials: G
authors.lastname: Boykow
authors.forename: Madhu
authors.initials: M
authors.lastname: Chintala
authors.forename: Carolyn
authors.initials: C
authors.lastname: Foster
authors.forename: April
authors.initials: A
authors.lastname: Smith-Torhan
authors.forename: Kevin
authors.initials: K
authors.lastname: Alton
authors.forename: Matthew
authors.initials: M
authors.lastname: Bryant
authors.forename: Yunsheng
authors.initials: Y
authors.lastname: Hsieh
authors.forename: Janice
authors.initials: J
authors.lastname: Lau
authors.forename: Jairam
authors.initials: J
authors.lastname: Palamanda
mesh_terms: D000818:Animals; D001682:Biological Availability; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D005663:Furans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D005663:Furans; D006575:Heterocyclic Compounds, 3-Ring; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D018179:Receptors, Thrombin; C517639:decahydro-7-hydroxy-3-methyl-4-(2-(5-(3-(trifluoromethyl)phenyl)-2-pyridinyl)ethenyl)naphtho(2,3-c)furan-1(3H)-one; D003577:Cytochrome P-450 Enzyme System