126330-91-4Relevant articles and documents
Piperazin-2-one amides as inhibitors of factor xa
-
, (2008/06/13)
Novel piperazin-2-one containing compounds of general formulae (I) or (II), including their pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivative having activity against mammalian factor Xa arc described. Compositions containing such compounds are also described. The compounds and the compositions are useful in vitro or in vivo for preventing or treating conditions in mammals characterized by undesired thrombosis.
Potent, orally active GPIIb/IIIa antagonists containing a nipecotic acid subunit. Structure-activity studies leading to the discovery of RWJ-53308
Hoekstra, William J.,Maryanoff, Bruce E.,Damiano, Bruce P.,Andrade-Gordon, Patricia,Cohen, Judith H.,Costanzo, Michael J.,Haertlein, Barbara J.,Hecker, Leonard R.,Hulshizer, Becky L.,Kauffman, Jack A.,Keane, Patricia,McComsey, David F.,Mitchell, John A.,Scott, Lorraine,Shah, Rekha D.,Yabut, Stephen C.
, p. 5254 - 5265 (2007/10/03)
Although intravenously administered antiplatelet fibrinogen receptor (GPIIb/IIIa) antagonists have become established in the acute-care clinical setting for the prevention of thrombosis, orally administered drugs for chronic use are still under development. Herein, we present details from our exploration of structure-activity surrounding the prototype fibrinogen receptor antagonist RWJ-50042 (racemate of 1), which was derived from a unique approach involving the γ-chain of fibrinogen (Hoekstra et al. J. Med. Chem. 1995, 38, 1582). Our analogue studies culminated in the discovery of RWJ-53308 (2), a potent, orally active GPIIb/IIIa antagonist. To progress from RWJ-50042 to a suitable candidate for clinical development, we conducted a series of optimization cycles that employed solid-phase parallel synthesis for the rapid, efficient preparation of nearly 250 analogues, which were assayed for fibrinogen receptor affinity and inhibition of platelet aggregation induced by four different activators. This strategy produced several promising analogues for advanced study, including 3-(3,4- methylenedioxybenzene)-β-amino acid analogue 3 (significant improved in vivo potency) and 3-(3-pyridyl)-β-amino acid 2 (significantly improved potency, oral absorption, and duration of action). In dogs, 2 displayed significant ex vivo antiplatelet activity on oral administration at 1.0 mg/kg, 16% systemic oral bioavailability, minimal metabolic transformation, and an excellent safety profile. Additionally, 2 was found to be efficacious in three in vivo thrombosis models: canine arteriovenous (AV) shunt (0.01-0.1 mg/kg, iv), guinea pig photoactivation-induced injury (0.3-3 mg/kg, iv), and guinea pig ferric chloride-induced injury (0.3-1 mg/kg, iv). On the basis of its noteworthy preclinical data, RWJ-53308 (2) was selected for clinical evaluation.
