Heterotricyclic himbacine analogs as potent, orally active thrombin receptor (protease activated receptor-1) antagonists.
Pursuing our earlier efforts in the himbacine-based thrombin receptor antagonist area, we have synthesized a series of compounds that incorporate heteroatoms in the C-ring of the tricyclic motif. This effort has resulted in the identification of several potent heterocyclic analogs with excellent affinity for the thrombin receptor. Several of these compounds demonstrated robust inhibition of platelet aggregation in an ex vivo model in cynomolgus monkeys following oral administration. A detailed profile of 28b, a benchmark compound in this series, with a Ki of 4.3 nM, is presented.
Chelliah
Mariappan V
MV
Central Nervous System and Cardiovascular Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. mariappan.chelliah@spcorp.com
Chackalamannil
Samuel
S
Xia
Yan
Y
Eagen
Keith
K
Clasby
Martin C
MC
Gao
Xiaobang
X
Greenlee
William
W
Ahn
Ho-Sam
HS
Agans-Fantuzzi
Jacqueline
J
Boykow
George
G
Hsieh
Yunsheng
Y
Bryant
Matthew
M
Palamanda
Jairam
J
Chan
Tze-Ming
TM
Hesk
David
D
Chintala
Madhu
M
D000284:Administration, Oral; D000470:Alkaloids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D001792:Blood Platelets / Q000378:metabolism; 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; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008252:Macaca fascicularis; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000470:Alkaloids; D005663:Furans; D006575:Heterocyclic Compounds, 3-Ring; D007546:Isoquinolines; D009281:Naphthalenes; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; C524272:decahydro-1-methyl-3-oxo-9-(2-(5-(3-fluorophenyl)-2-pyridinyl)ethenyl)furo(3,4-g)isoquinoline-6(3H)-carboxylic acid ethyl ester; C048172:himbacine