Biomaterial Database

Synthesis and initial evaluation of novel, non-peptidic antagonists of the alpha(v)-integrins alpha(v)beta(3) and alpha(v)beta(5). 2009

Jeffrey J Letourneau, and Jinqi Liu, and Michael H J Ohlmeyer, and Chris Riviello, and Yajing Rong, and Hong Li, and Kenneth C Appell, and Shalini Bansal, and Biji Jacob, and Angela Wong, and Maria L Webb

Department of Chemistry, Pharmacopeia, Inc., PO Box 5350, Princeton, NJ 08543, USA. jletourn@pcop.com

The discovery, synthesis and preliminary SAR of a novel class of non-peptidic antagonists of the alpha(v)-integrins alpha(v)beta(3) and alpha(v)beta(5) is described. High-throughput screening of an extensive series of ECLiPStrade mark compound libraries led to the identification of compound 1 as a dual inhibitor of the alpha(v)-integrins alpha(v)beta(3) and alpha(v)beta(5). Optimization of compound 1 involving, in part, introduction of two novel constraints led to the discovery of compounds 15a and 15b with reduced PSA and much improved potency for both the alpha(v)beta(3) and alpha(v)beta(5) integrins. Compounds 15a and 15b were shown to have promising activity in functional cellular assays and compound 15a also exhibited a promising Caco-2 permeability profile.

UI	MeSH Term	Description	Entries
D002460	Cell Line	Established cell cultures that have the potential to propagate indefinitely.	Cell Lines,Line, Cell,Lines, Cell
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D001682	Biological Availability	The extent to which the active ingredient of a drug dosage form becomes available at the site of drug action or in a biological medium believed to reflect accessibility to a site of action.	Availability Equivalency,Bioavailability,Physiologic Availability,Availability, Biologic,Availability, Biological,Availability, Physiologic,Biologic Availability,Availabilities, Biologic,Availabilities, Biological,Availabilities, Physiologic,Availability Equivalencies,Bioavailabilities,Biologic Availabilities,Biological Availabilities,Equivalencies, Availability,Equivalency, Availability,Physiologic Availabilities
D013329	Structure-Activity Relationship	The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.	Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D047028	Macrocyclic Compounds	Cyclic compounds with a ring size of approximately 1-4 dozen atoms.	Macrocycle Compounds,Spherands,Torands,Compounds, Macrocycle,Compounds, Macrocyclic
D019030	Receptors, Vitronectin	Receptors such as INTEGRIN ALPHAVBETA3 that bind VITRONECTIN with high affinity and play a role in cell migration. They also bind FIBRINOGEN; VON WILLEBRAND FACTOR; osteopontin; and THROMBOSPONDINS.	Vitronectin Receptors
D039302	Integrin alphaVbeta3	An integrin that binds to a variety of plasma and extracellular matrix proteins containing the conserved RGD amino acid sequence and modulates cell adhesion. Integrin alphavbeta3 is highly expressed in OSTEOCLASTS where it may play role in BONE RESORPTION. It is also abundant in vascular smooth muscle and endothelial cells, and in some tumor cells, where it is involved in angiogenesis and cell migration. Although often referred to as the vitronectin receptor there is more than one receptor for vitronectin (RECEPTORS, VITRONECTIN).	Integrin alpha-v beta-3,Receptors, alpha-v beta-3 Integrin,Vitronectin Receptor,alpha-v beta-3 Integrin Receptors,Integrin alpha v beta 3,Receptor, Vitronectin,Receptors, alpha v beta 3 Integrin,alpha v beta 3 Integrin Receptors,alpha-v beta-3, Integrin,alphaVbeta3, Integrin,beta-3, Integrin alpha-v