Potent, Orally Active GPIIb/IIIa Antagonists Containing a Nipecotic Acid Subunit. Structure−Activity Studies Leading to the Discovery of RWJ-53308

Abstract

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 gamma-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)-beta-amino acid analogue 3 (significant improved in vivo potency) and 3-(3-pyridyl)-beta-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.

Effect of the PlA2 alloantigen on the function of β3-integrins in platelets

“…RWJ 53308 is a peptidomimetic whose structure is based on the K-Q-A-G-D sequence present at the carboxyl terminus of the fibrinogen ␥ chain. 16 Platelets in citrated whole blood were stained with 2 anti-␣ IIb ␤ 3 mAbs: Mab1, whose binding was not affected by RWJ 53308, and Mab2, whose binding to ␣ IIb ␤ 3 is inhibited by RWJ 53308. Flow cytometry measurements were converted to occupied ␣ IIb ␤ 3 complexes using microbeads coated with known amounts of FITC.…”

“…We also studied the effect of Pl A allotype on the ability of the low-molecular-weight ␣ IIb ␤ 3 antagonist RWJ 53308 to inhibit macroscopic platelet aggregation. 16 We first determined whether there were differences in binding of the compound to platelets according to their Pl A allotype. As seen in Figure 7A, RWJ 53308 bound equally well to platelets regardless of Pl A allotype.…”

18F-GP1, a Novel PET Tracer Designed for High-Sensitivity, Low-Background Detection of Thrombi

“…In a growing thrombus, the key step of platelet aggregation is characterized by the binding of activated GPIIb/IIIa to blood fibrinogen domains containing the arginine-glycine-aspartic acid (RGD) motif, which results in crosslinking. The design and development of glycoprotein IIb/IIIa inhibitors has attracted a considerable amount of interest in pharmacologic research with respect to antiplatelet and antithrombotic activity (12)(13)(14)(15)(16)(17). GPIIb/IIIa antagonists are commercially available, for example, abciximab (ReoPro, Centocor; Eli Lilly), eptifibatide (Integrilin; GlaxoSmithKline), and tirofiban (Aggrastat; Correvio International Sarl).…”

?-Amino Acids: Role in Human Biology and Medicinal Chemistry - A Review

“…It holds an (S)-3-amino-3-(3-pyridyl) propanoic acid subunit. Derivatives of (R)-3-amino-3-phenylpropanoic acid, (R)-3-amino-3-(3-pyridyl) propanoic acid and (R)-3-amino-5-phenylpentanoic acid have been tested as hepatitis C virus (HCV) NS5B polymerase inhibitors, a valid target for antiviral therapy against HCV [47,48]. (R)-3-amino-3-phenylpropanoic acid and (R)-3-amino-3-benzo (1,3) dioxol-5yl propanoic acid have introduced into anti-inflammatory bradykinin B1 receptor (protein coupled receptor) antagonists [49,50].…”