Design and evaluation of nonpeptide fibrinogen gamma-chain based GPIIb/IIIa antagonists.
Two series of nonpeptide turn mimetics were designed by analysis of the solution NMR structure of the 385-411 sequence of the gamma-chain of fibrinogen. These compounds, based on the KQAGD (Lys-Gln-Ala-Gly-Asp, 406-410) sequence, were synthesized and studied in vitro. The most interesting compound from our study, RWJ 50042 (25), exhibits potent inhibition of fibrinogen binding to GPIIb/IIIa (IC50 = 0.009 microM), as well as thrombin- or collagen-induced platelet aggregation (IC50 = 0.76, 0.14 microM). Since the 400-411 sequence is required for gamma-chain bioactivity and is a unique recognition sequence among ligands for integrins, vis-a-vis other RGD (Arg-Gly-Asp)-presenting proteins, these turn mimetics may represent a new, selective approach to antagonism of the fibrinogen receptor.
Hoekstra
W J
WJ
R. W. Johnson Pharmaceutical Research Institute, Pennsylvania 19477, USA.
Beavers
M P
MP
Andrade-Gordon
P
P
Evangelisto
M F
MF
Keane
P M
PM
Press
J B
JB
Tomko
K A
KA
Fan
F
F
Kloczewiak
M
M
Mayo
K H
KH
D000595:Amino Acid Sequence; D015195:Drug Design; D005340:Fibrinogen / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*
D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D005340:Fibrinogen