Design of a new class of orally active fibrinogen receptor antagonists.
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.
Klein
S I
SI
Department of Cardiovascular Research, Rhône-Poulenc Rorer Central Research, Collegeville, Pennsylvania 19426, USA.
Molino
B F
BF
Czekaj
M
M
Gardner
C J
CJ
Chu
V
V
Brown
K
K
Sabatino
R D
RD
Bostwick
J S
JS
Kasiewski
C
C
Bentley
R
R
Windisch
V
V
Perrone
M
M
Dunwiddie
C T
CT
Leadley
R J
RJ
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
D009842:Oligopeptides; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex