Nonpeptide glycoprotein IIB/IIIA inhibitors. 19. A new design paradigm employing linearly minimized, centrally constrained, exosite inhibitors.
A new series of potent, linearly-minimized, orally active, selective GPIIb/IIIa inhibitors is identified. Thus 15 (L-750,034) achieves interaction via a constrained, non-turned conformation that maintains the proper distance between its charged termini and full sulfonamide exosite interaction. The diminutive stature and the proposed linear conformation of L-750,034 define a new paradigm for the conceptualization of RGD mimics.
Hartman
G D
GD
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
Duggan
M E
ME
Hoffman
W F
WF
Meissner
R J
RJ
Perkins
J J
JJ
Zartman
A E
AE
Naylor-Olsen
A M
AM
Cook
J J
JJ
Glass
J D
JD
Lynch
R J
RJ
Zhang
G
G
Gould
R J
RJ
D001549:Benzamides / Q000494:pharmacology*; D015195:Drug Design; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008958:Models, Molecular; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D013997:Time Factors
D001549:Benzamides; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C103544:4-hydroxybenzamide