Nonpeptide alpha(v)beta(3) antagonists. Part 2: constrained glycyl amides derived from the RGD tripeptide.
Mimetics of the RGD tripeptide are described that are potent, selective antagonists of the integrin receptor, alpha(v)beta(3). The use of the 5,6,7,8-tetrahydro[1,8]naphthyridine group as a potency-enhancing N-terminus is demonstrated. Two 3-substituted-3-amino-propionic acids previously contained in alpha(IIb)beta(3) antagonists were utilized to enhance binding affinity and functional activity for the targeted receptor. Further affinity increases were then achieved through the use of cyclic glycyl amide bond constraints.
Meissner
Robert S
RS
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. robert_meissner@merck.com
Perkins
James J
JJ
Duong
Le T
LT
Hartman
George D
GD
Hoffman
William F
WF
Huff
Joel R
JR
Ihle
Nathan C
NC
Leu
Chih Tai
CT
Nagy
Rose M
RM
Naylor-Olsen
Adel
A
Rodan
Gideon A
GA
Rodan
Sevgi B
SB
Whitman
David B
DB
Wesolowski
Gregg A
GA
Duggan
Mark E
ME
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020128:Inhibitory Concentration 50; D008968:Molecular Conformation; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010024:Osteoporosis / Q000517:prevention & control; D010974:Platelet Aggregation / Q000187:drug effects; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000577:Amides; D009842:Oligopeptides; D019030:Receptors, Vitronectin; C047981:arginyl-glycyl-aspartic acid