Disubstituted indazoles as potent antagonists of the integrin alpha(v)beta(3)

• Published in: Journal of medicinal chemistry 2000-01, Vol.43 (1), p.41-58
• Main Authors: Batt, D G, Petraitis, J J, Houghton, G C, Modi, D P, Cain, G A, Corjay, M H, Mousa, S A, Bouchard, P J, Forsythe, M S, Harlow, P P, Barbera, F A, Spitz, S M, Wexler, R R, Jadhav, P K
• Format: Article
• Language: English
• Subjects: Cell Adhesion - drug effects; Cell Line; Fibrinogen - metabolism; Humans; In Vitro Techniques; Indazoles - chemical synthesis; Indazoles - chemistry; Indazoles - pharmacology; Models, Molecular; Platelet Aggregation - drug effects; Platelet Glycoprotein GPIIb-IIIa Complex - antagonists & inhibitors; Receptors, Vitronectin - antagonists & inhibitors; Structure-Activity Relationship
• ISSN: 0022-2623
• DOI: 10.1021/jm990049j

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.