title: Emergence of Small-Molecule Non-RGD-Mimetic Inhibitors for RGD Integrins.
abstract: The RGD integrins are recognized therapeutic targets for thrombosis, fibrosis, and cancer, among others. Current inhibitors are designed to mimic the tripeptide sequence (arginine-glycine-aspartic acid) of the natural ligands; however, the RGD-mimetic antagonists for αIIbβ3have been shown to cause partial agonism, leading to the opposite pharmacological effect. The challenge of obtaining oral activity and synthetic tractability with RGD-mimetic molecules, along with the issues relating to pharmacology, has left integrin therapeutics in need of a new strategy. Recently, a new generation of inhibitor has emerged that lacks the RGD-mimetic. This review will discuss the discovery of these non-RGD-mimetic inhibitors and the progress that has been made in this promising new chemotype.
authors.affiliation: WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde , Thomas Graham Building, 295 Cathedral Street, Glasgow, G1 1XL, U.K.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Miller
authors.affiliation: Fibrosis Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: John M
authors.initials: JM
authors.lastname: Pritchard
authors.affiliation: Fibrosis Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
authors.forename: Simon J F
authors.initials: SJF
authors.lastname: Macdonald
authors.affiliation: WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde , Thomas Graham Building, 295 Cathedral Street, Glasgow, G1 1XL, U.K.
authors.forename: Craig
authors.identifier: 0000-0002-6567-8272
authors.initials: C
authors.lastname: Jamieson
authors.affiliation: WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde , Thomas Graham Building, 295 Cathedral Street, Glasgow, G1 1XL, U.K.
authors.forename: Allan J B
authors.identifier: 0000-0002-1582-4286
authors.initials: AJB
authors.lastname: Watson
mesh_terms: D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry*
chemical_list: D016023:Integrins; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid