title: Design of a new class of orally active fibrinogen receptor antagonists.
abstract: The integrin receptor recognition sequence Arg-Gly-Asp was successfully used as a template from which to develop a series of potent, selective, orally active, peptide-based fibrinogen receptor antagonists with a long duration of action. Simple modifications centered on the Arg and Gly residues quickly led to a modified peptide (1) with significantly enhanced ability to inhibit in vitro platelet aggregation. Substitution of the guanidino group in 1 by piperidine provided 3, which showed not only a further increase in potency but also a modest degree of oral efficacy. Finally, exploration of the nature of the C-terminal amino acid, with respect to its side-chain functionality and the carboxy terminus, yielded a group of molecules that showed excellent in vitro potency for inhibiting platelet aggregation, excellent integrin selectivity, a high level of oral efficacy, and an extended duration of action.
authors.affiliation: Department of Cardiovascular Research, Rhône-Poulenc Rorer Central Research, Collegeville, Pennsylvania 19426, USA.
authors.forename: S I
authors.initials: SI
authors.lastname: Klein
authors.forename: B F
authors.initials: BF
authors.lastname: Molino
authors.forename: M
authors.initials: M
authors.lastname: Czekaj
authors.forename: C J
authors.initials: CJ
authors.lastname: Gardner
authors.forename: V
authors.initials: V
authors.lastname: Chu
authors.forename: K
authors.initials: K
authors.lastname: Brown
authors.forename: R D
authors.initials: RD
authors.lastname: Sabatino
authors.forename: J S
authors.initials: JS
authors.lastname: Bostwick
authors.forename: C
authors.initials: C
authors.lastname: Kasiewski
authors.forename: R
authors.initials: R
authors.lastname: Bentley
authors.forename: V
authors.initials: V
authors.lastname: Windisch
authors.forename: M
authors.initials: M
authors.lastname: Perrone
authors.forename: C T
authors.initials: CT
authors.lastname: Dunwiddie
authors.forename: R J
authors.initials: RJ
authors.lastname: Leadley
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D004285:Dogs; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009842:Oligopeptides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D015539:Platelet Activation; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects
chemical_list: D009842:Oligopeptides; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex