title: Nonpeptide alpha(v)beta(3) antagonists. Part 2: constrained glycyl amides derived from the RGD tripeptide.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. robert_meissner@merck.com
authors.forename: Robert S
authors.initials: RS
authors.lastname: Meissner
authors.forename: James J
authors.initials: JJ
authors.lastname: Perkins
authors.forename: Le T
authors.initials: LT
authors.lastname: Duong
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: William F
authors.initials: WF
authors.lastname: Hoffman
authors.forename: Joel R
authors.initials: JR
authors.lastname: Huff
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Ihle
authors.forename: Chih Tai
authors.initials: CT
authors.lastname: Leu
authors.forename: Rose M
authors.initials: RM
authors.lastname: Nagy
authors.forename: Adel
authors.initials: A
authors.lastname: Naylor-Olsen
authors.forename: Gideon A
authors.initials: GA
authors.lastname: Rodan
authors.forename: Sevgi B
authors.initials: SB
authors.lastname: Rodan
authors.forename: David B
authors.initials: DB
authors.lastname: Whitman
authors.forename: Gregg A
authors.initials: GA
authors.lastname: Wesolowski
authors.forename: Mark E
authors.initials: ME
authors.lastname: Duggan
mesh_terms: 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
chemical_list: D000577:Amides; D009842:Oligopeptides; D019030:Receptors, Vitronectin; C047981:arginyl-glycyl-aspartic acid