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.