Disubstituted Indazoles as Potent Antagonists of the Integrin αvβ3

Autor:	Patricia P Harlow, Susan M. Spitz, Mark S. Forsythe, Ruth R. Wexler, Martha H. Corjay, Joseph J. Petraitis, Peter J. Bouchard, Gregory C. Houghton, Shaker A. Mousa, Prabhakar K. Jadhav, Frank A. Barbera, Douglas G. Batt, Dilip P. Modi, Gary A. Cain
Rok vydání:	1999
Předmět:	Indazole biology Bicyclic molecule Stereochemistry Integrin Chemical synthesis chemistry.chemical_compound chemistry Drug Discovery biology.protein Molecular Medicine Moiety Selectivity Lead compound Linker
Zdroj:	Journal of Medicinal Chemistry. 43:41-58
ISSN:	1520-4804 0022-2623
DOI:	10.1021/jm990049j
Popis:	A new series of indazole-containing αvβ3 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 β3-transfected 293 cells to fibrinogen and to selectivity for αvβ3 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 αvβ3 (IC50 2.3 nM) with 9-fold selectivity over GPIIbIIIa.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::9cb1e0dfb66424a070cd1095d9734008 https://doi.org/10.1021/jm990049j Zobrazit plný text záznamu