Design of a New Class of Orally Active Fibrinogen Receptor Antagonists

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• 作者：Scott I. Klein ; Bruce F. Molino ; Mark Czekaj ; Charles J. Gardner ; Valeria Chu ; Karen Brown ; Ralph D. Sabatino ; Jeffrey S. Bostwick ; Charles Kasiewski ; Ross Bentley ; Vincent Windisch ; Mark Perrone ; Chr
• 刊名：Journal of Medicinal Chemistry
• 出版年：1998
• 出版时间：July 2, 1998
• 年：1998
• 卷：41
• 期：14
• 页码：2492 - 2502
• 全文大小：212K
• 年卷期：v.41,no.14(July 2, 1998)
• ISSN：1520-4804

文摘

The integrin receptor recognition sequence Arg-Gly-Asp wassuccessfully used as a templatefrom which to develop a series of potent, selective, orally active,peptide-based fibrinogenreceptor antagonists with a long duration of action. Simplemodifications centered on the Argand Gly residues quickly led to a modified peptide (1) withsignificantly enhanced ability toinhibit in vitro platelet aggregation. Substitution of theguanidino group in 1 by piperidineprovided 3, which showed not only a further increase inpotency but also a modest degree oforal efficacy. Finally, exploration of the nature of theC-terminal amino acid, with respect toits side-chain functionality and the carboxy terminus, yielded a groupof molecules that showedexcellent in vitro potency for inhibiting platelet aggregation,excellent integrin selectivity, ahigh level of oral efficacy, and an extended duration ofaction.