Potent, Selective, Orally Active 3-Oxo-1,4-benzodiazepine GPIIb/IIIa Integrin Antagonists

Abstract

The role of GPIIb/IIIa antagonists in the prevention of thrombosis has gained increasing attention in recent years. 1,2 Since chronic oral administration of GPIIb/IIIa antagonists could, in principle, address myocardial infarction and stroke, the number one and number three leading causes of death in the United States, 3 intense interest has developed over the discovery of orally active GPIIb/IIIa antagonists. The peptide SK&F 107260 4 (1, depicted in Table 1), shown to contain a turn-extendedturn conformation about the critical residues (NMe)Arg-Gly-Asp, 5 was one of a series of cyclic peptide antagonists that defined a peptide pharmacophore model 6 which was employed in the design 7 of a series of 8-substituted 3-oxo-1,4-benzodiazepine GPIIb/IIIa antagonists, typified by the 8-(p-amidinophenyl)amido compounds 2 and 3. 7,8 Extensive investigations of the 8-substituted analogs have led to the discovery of several analogs which displayed oral activity but with limited oral duration of action.We have concurrently explored a series of 7-substi-

Nanomolar Small Molecule Inhibitors for αvβ6, αvβ5, and αvβ3 Integrins

“…In compound 13, the guanidino group itself served this role. The acidic, C-terminal component of the molecules is formed either by an aromatic amino acid (8-15) or a substituted glutaric acid group (6,7). The glycine spacer is retained in 9-12 and 14.…”

“…This has complicated the discovery of specific inhibitors. For example, at least the five Rv-integrins ( 1, 3, 5,6,8), as well as integrins RIIb 3, R5 1, and R8 1 bind their ligands via the RGD sequence. For some of these integrins, the specificity of interaction with the ligand involves a supplementary site distant from the RGD site.…”

The Significance of G Protein-Coupled Receptor Crystallography for Drug Discovery

“…This work used conformationally constrained cyclic peptides bearing a similar small binding motif to inform the design of small molecule leads that had remarkably high selectivity for closely related integrin receptor subtypes (Engleman et al, 1996;Samanen, 1996;Samanen et al, 1996;Keenan et al, 1997).…”

Molecular Mediators of α_vβ₃-Induced Endothelial Cell Survival

“…In addition to anoikis due to general loss of cell anchorage, distinct integrins have been implicated in protection against apoptosis in different cell types [2,3,4,5,6,7]. The integrin α v β 3 is rapidly upregulated in cells mediating general tissue remodeling processes, and has been implicated in mediating survival signals important in osteoporosis, restenosis, atherosclerosis, angiogenesis and tumor metastasis [8,9,10,11,12]. α v β 3 is expressed on angiogenic, but not quiescent ECs, and has been implicated as an important mediator of endothelial cell survival during angiogenesis [13].…”