title: Small molecule inhibitors of integrin alpha2beta1.
abstract: Interactions between the integrin, alpha2beta1, and extracellular matrix (ECM), particularly collagen, play a pivotal role in platelet adhesion and thrombus formation. Platelets interact with collagen in the subendothelial matrix that is exposed by vascular damage. To evaluate the potential of alpha2beta1 inhibitors for anticancer and antithrombotic applications, we have developed a series of small molecule inhibitors of this integrin based on a prolyl-2,3-diaminopropionic acid (DAP) scaffold using solid-phase parallel synthesis. A benzenesulfonamide substituent at the N-terminus of the dipepetide and a benzyl urea at the DAP side chain resulted in tight and highly selective inhibition of alpha2beta1-mediated adhesion of human platelets and other cells to collagen.
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Sungwook
authors.initials: S
authors.lastname: Choi
authors.forename: Gaston
authors.initials: G
authors.lastname: Vilaire
authors.forename: Cezary
authors.initials: C
authors.lastname: Marcinkiewicz
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Winkler
authors.forename: Joel S
authors.initials: JS
authors.lastname: Bennett
authors.forename: William F
authors.initials: WF
authors.lastname: DeGrado
mesh_terms: D001665:Binding Sites; D001792:Blood Platelets / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects; D024042:Collagen Type I / Q000502:physiology; D024141:Collagen Type IV / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D038982:Integrin alpha2beta1 / Q000037:antagonists & inhibitors*; D020014:K562 Cells; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D024042:Collagen Type I; D024141:Collagen Type IV; D038982:Integrin alpha2beta1; D011994:Recombinant Proteins; D013449:Sulfonamides; D015091:beta-Alanine; C011757:2,3-diaminopropionic acid; D011392:Proline