title: Isoxazolines as potent antagonists of the integrin alpha(v)beta(3).
abstract: Starting with lead compound 2, we sought to increase the selectivity for alpha(v)beta(3)-mediated cell adhesion by examining the effects of structural changes in both the guanidine mimetic and the substituent alpha to the carboxylate. To prepare some of the desired aminoimidazoles, a novel reductive amination utilizing a trityl-protected aminoimidazole was developed. It was found that guanidine mimetics with a wide range of pK(a)'s were potent antagonists of alpha(v)beta(3). In general, it appeared that an acylated 2-aminoimidazole guanidine mimetic imparted excellent selectivity for alpha(v)beta(3)-mediated adhesion versus alpha(IIb)beta(3)-mediated platelet aggregation, with selectivity of approximately 3 orders of magnitude observed for compounds 3g and 3h. It was also found in this series that the alpha-substituent was required for potent activity and that 2,6-disubstituted arylsulfonamides were optimal. In addition, the selective alpha(v)beta(3) antagonist 3h was found to be a potent inhibitor of alpha(v)beta(3)-mediated cell migration.
authors.affiliation: DuPont Pharmaceuticals Company, P.O. Box 80500, Wilmington, Delaware 19880-0500, USA.
authors.forename: W J
authors.initials: WJ
authors.lastname: Pitts
authors.forename: J
authors.initials: J
authors.lastname: Wityak
authors.forename: J M
authors.initials: JM
authors.lastname: Smallheer
authors.forename: A E
authors.initials: AE
authors.lastname: Tobin
authors.forename: J W
authors.initials: JW
authors.lastname: Jetter
authors.forename: J S
authors.initials: JS
authors.lastname: Buynitsky
authors.forename: P P
authors.initials: PP
authors.lastname: Harlow
authors.forename: K A
authors.initials: KA
authors.lastname: Solomon
authors.forename: M H
authors.initials: MH
authors.lastname: Corjay
authors.forename: S A
authors.initials: SA
authors.lastname: Mousa
authors.forename: R R
authors.initials: RR
authors.lastname: Wexler
authors.forename: P K
authors.initials: PK
authors.lastname: Jadhav
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D006146:Guanidines / Q000737:chemistry; D006801:Humans; D006965:Hyperplasia / Q000378:metabolism; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D019096:Vitronectin / Q000494:pharmacology; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C403759:DMP 745; D006146:Guanidines; D007555:Isoxazoles; D019030:Receptors, Vitronectin; D019096:Vitronectin; C104209:XR 299; D015091:beta-Alanine