title: Disubstituted indazoles as potent antagonists of the integrin alpha(v)beta(3).
abstract: A new series of indazole-containing alpha(v)beta(3) integrin antagonists is described. Starting with lead compound 18a, variations in a number of structural features were explored with respect to inhibition of the binding of beta(3)-transfected 293 cells to fibrinogen and to selectivity for alpha(v)beta(3) over GPIIbIIIa, another RGD-binding integrin. Indazoles attached to a 2-aminopyridine or 2-aminoimidazole by a propylene linker at the indazole 1-position and to a diaminopropionate derivative via a 5-carboxylate amide provided the best potency with moderate selectivity. Several differences in the SAR of the diaminopropionate moiety were observed between this series and a series of isoxazoline-based selective GPIIbIIIa antagonists. Compound 34a (SM256) was a potent antagonist of alpha(v)beta(3) (IC(50) 2.3 nM) with 9-fold selectivity over GPIIbIIIa.
authors.affiliation: DuPont Pharmaceuticals Company, P.O. Box 80500, Wilmington, Delaware 19880-0500, USA. battdg@a1.lldmpc.umc.dupont.com
authors.forename: D G
authors.initials: DG
authors.lastname: Batt
authors.forename: J J
authors.initials: JJ
authors.lastname: Petraitis
authors.forename: G C
authors.initials: GC
authors.lastname: Houghton
authors.forename: D P
authors.initials: DP
authors.lastname: Modi
authors.forename: G A
authors.initials: GA
authors.lastname: Cain
authors.forename: M H
authors.initials: MH
authors.lastname: Corjay
authors.forename: S A
authors.initials: SA
authors.lastname: Mousa
authors.forename: P J
authors.initials: PJ
authors.lastname: Bouchard
authors.forename: M S
authors.initials: MS
authors.lastname: Forsythe
authors.forename: P P
authors.initials: PP
authors.lastname: Harlow
authors.forename: F A
authors.initials: FA
authors.lastname: Barbera
authors.forename: S M
authors.initials: SM
authors.lastname: Spitz
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; D002460:Cell Line; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D007191:Indazoles; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019030:Receptors, Vitronectin; D005340:Fibrinogen