Document Report Card

ID: ALA3091329

Journal: ACS Med Chem Lett

Title: Discovery of tetrahydroisoquinoline-based CXCR4 antagonists.

Authors: Truax VM, Zhao H, Katzman BM, Prosser AR, Alcaraz AA, Saindane MT, Howard RB, Culver D, Arrendale RF, Gruddanti PR, Evers TJ, Natchus MG, Snyder JP, Liotta DC, Wilson LJ.

Abstract: A de novo hit-to-lead effort involving the redesign of benzimidazole-containing antagonists of the CXCR4 receptor resulted in the discovery of a novel series of 1,2,3,4-tetrahydroisoquinoline (TIQ) analogues. In general, this series of compounds show good potencies (3-650 nM) in assays involving CXCR4 function, including both inhibition of attachment of X4 HIV-1IIIB virus in MAGI-CCR5/CXCR4 cells and inhibition of calcium release in Chem-1 cells. Series profiling permitted the identification of TIQ-(R)-stereoisomer 15 as a potent and selective CXCR4 antagonist lead candidate with a promising in vitro profile. The drug-like properties of 15 were determined in ADME in vitro studies, revealing low metabolic liability potential. Further in vivo evaluations included pharmacokinetic experiments in rats and mice, where 15 was shown to have oral bioavailability (F = 63%) and resulted in the mobilization of white blood cells (WBCs) in a dose-dependent manner.

CiteXplore: 24936240

DOI: 10.1021/ml400183q