title: Heterotricyclic himbacine analogs as potent, orally active thrombin receptor (protease activated receptor-1) antagonists.
abstract: 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.
authors.affiliation: Central Nervous System and Cardiovascular Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. mariappan.chelliah@spcorp.com
authors.forename: Mariappan V
authors.initials: MV
authors.lastname: Chelliah
authors.forename: Samuel
authors.initials: S
authors.lastname: Chackalamannil
authors.forename: Yan
authors.initials: Y
authors.lastname: Xia
authors.forename: Keith
authors.initials: K
authors.lastname: Eagen
authors.forename: Martin C
authors.initials: MC
authors.lastname: Clasby
authors.forename: Xiaobang
authors.initials: X
authors.lastname: Gao
authors.forename: William
authors.initials: W
authors.lastname: Greenlee
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: Yunsheng
authors.initials: Y
authors.lastname: Hsieh
authors.forename: Matthew
authors.initials: M
authors.lastname: Bryant
authors.forename: Jairam
authors.initials: J
authors.lastname: Palamanda
authors.forename: Tze-Ming
authors.initials: TM
authors.lastname: Chan
authors.forename: David
authors.initials: D
authors.lastname: Hesk
authors.forename: Madhu
authors.initials: M
authors.lastname: Chintala
mesh_terms: 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
chemical_list: 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