Metabolism-based identification of a potent thrombin receptor antagonist.
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.
Clasby
Martin C
MC
Central Nervous System and Cardiovascular Chemical Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
Chackalamannil
Samuel
S
Czarniecki
Michael
M
Doller
Dario
D
Eagen
Keith
K
Greenlee
William
W
Kao
Grace
G
Lin
Yan
Y
Tsai
Hsingan
H
Xia
Yan
Y
Ahn
Ho-Sam
HS
Agans-Fantuzzi
Jacqueline
J
Boykow
George
G
Chintala
Madhu
M
Foster
Carolyn
C
Smith-Torhan
April
A
Alton
Kevin
K
Bryant
Matthew
M
Hsieh
Yunsheng
Y
Lau
Janice
J
Palamanda
Jairam
J
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
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