Solid-phase parallel synthesis applied to lead optimization: Discovery of potent analogues of the GPIIb/IIIa antagonist RWJ-50042

Hoekstra, William J.; Maryanoff, Bruce E.; Andrade‐Gordon, Patricia; Cohen, Judith H.; Costanzo, Michael J.; Damiano, Bruce P.; Haertlein, Barbara J.; Harris, Bruce D.; Kauffman, Jack A.; Keane, Patricia M.; McComsey, David F.; Villani, Frank J.; Yabut, Stephen C.

doi:10.1016/0960-894x(96)00438-6

Cited by 32 publications

(17 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Synthesis of Analogues of RWJ-50042. Given the competitive environment surrounding the GPIIb/IIIa area of antithrombotic therapy, we had pursued synthetic methodology to expedite the rapid preparation of analogues of 1 : namely, solid-supported parallel organic synthesis. , In our preliminary report, we used a synthetic procedure involving N-terminal attachment of the substrate to a 2-chlorotrityl resin and found that substitution on the β-amino acid carbon of 1 with an arene is important for potency improvement . Compound 3 represented early success from the parallel synthesis arrays and sufficient quantities were then obtained by enantioselective synthesis.…”

Section: Resultsmentioning

confidence: 99%

“…Alternatively, asymmetric synthesis could be employed. For instance, the synthesis of the 3-(3,4-methylenedioxybenzene)-β-amino ester for 3 was accomplished in high diastereomeric excess by using an asymmetric Michael addition of lithiated α-methylbenzylamine to the requisite cinnamate. , For pyridyl-containing 6 , however, removal of the α-methylbenzyl chiral auxiliary group resulted in poor yields. A better method here was resolution of phenylacetamide 5 with penicillin amidase (Scheme ) .…”

Section: Resultsmentioning

confidence: 99%

“…Although nipecotamide 1 exhibited oral activity, it had modest potency and a short duration of action in vivo (ex vivo inhibition of platelet aggregation following oral administration to dogs at 10 mg/kg). A well-focused optimization program that relied heavily on the rapid, solid-phase parallel synthesis of analogues solved this problem quickly and delivered a potent clinical candidate, RWJ-53308 ( 2 ). Significantly, this compound can be dosed both intravenously and orally, has a good duration of action, and demonstrates excellent safety characteristics.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 1999

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 1999

Self Cite

View full text Add to dashboard Cite

show abstract

“…Tertiary amide of the structure can offer a conformational constraint, for example, compound 55 (IC 50 = 0.016 ± 0.001 μM, human PRP/ADP) [61,62].…”

Section: Lead Compound: Rgdmentioning

confidence: 99%

“…Large hydrophobic groups in this part of the molecule afforded the best activity. The new injectable GPIIb/IIIa antagonist FK419 (53), which is now under clinical trials, has the virtue of reduced prolongation of bleeding time [61,62].…”

Section: Lead Compound: Rgdmentioning

confidence: 99%

Progress in the Research of GPIIb/IIIa Antagonists

et al. 2015

View full text Add to dashboard Cite

This review covers the recent advances in the development of small RGD (Arg-Gly-Asp sequence) containing peptides and their mimetics as potential antithrombotic agents. Glycoprotein IIb/IIIa (GPIIb/IIIa) antagonists include monoclonal antibodies, RGD peptides, peptide hybrids and nonpeptide mimetics. The current trend in the development of nonpeptide mimetics is clearly directed toward orally active and safe antithrombotic drug candidates. But several nonpeptide mimetics, being evaluated for their oral activity in human clinical trials, are currently not approved for clinical use due to poor safety profile. It is expected that newer and more effective nonpeptide mimetics will be developed in the near future.

show abstract

Solid Phase Chemistry

Bannwarth¹

2000

Combinatorial Chemistry

View full text Add to dashboard Cite

Solid-phase parallel synthesis applied to lead optimization: Discovery of potent analogues of the GPIIb/IIIa antagonist RWJ-50042

Cited by 32 publications

References 15 publications

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

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

Progress in the Research of GPIIb/IIIa Antagonists

Solid Phase Chemistry

Contact Info

Product

Resources

About