Non-peptide RGD surrogates which mimic a Gly-Asp beta-turn: potent antagonists of platelet glycoprotein IIb-IIIa.
Cyclic heptapeptide 1, which contains an Arg-Gly-Asp sequence, has good affinity for the platelet receptor GPIIb-IIIa and was chosen for study by 1H NMR techniques. The key RGD sequence of this molecule was found to reside in a conformationally defined type II' Gly-Asp beta-turn, and this information was used in the design of simple non-peptide RGD mimics. Disubstituted isoquinolones, bearing an acidic side chain at position 2 and a basic side chain at position 6, were prepared and were found to have modest affinity for GPIIb-IIIa. Systematic modification of the basic residue contained in these molecules yielded compounds with high affinity for GPIIb-IIIa.
Fisher
M J
MJ
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
Gunn
B
B
Harms
C S
CS
Kline
A D
AD
Mullaney
J T
JT
Nunes
A
A
Scarborough
R M
RM
Arfsten
A E
AE
Skelton
M A
MA
Um
S L
SL
Utterback
B G
BG
Jakubowski
J A
JA
D001224:Aspartic Acid; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D005998:Glycine; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D010974:Platelet Aggregation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship
D009842:Oligopeptides; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D001224:Aspartic Acid; C047981:arginyl-glycyl-aspartic acid; D005998:Glycine