Discovery of tetrahydroisoquinoline-based CXCR4 antagonists

ACS Med Chem Lett. 2013 Sep 5;4(11):1025-30. doi: 10.1021/ml400183q.

Valarie M Truax ¹, Huanyu Zhao ², Brooke M Katzman ¹, Anthony R Prosser ¹, Ana A Alcaraz ¹, Manohar T Saindane ², Randy B Howard ², Deborah Culver ², Richard F Arrendale ², Prahbakar R Gruddanti ², Taylor J Evers ², Michael G Natchus ², James P Snyder ¹, Dennis C Liotta ³, Lawrence J Wilson ¹

Affiliations

1 Department of Chemistry, Emory University , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
2 Emory Institute for Drug Development, 954 Gatewood Road NE, Atlanta, Georgia 30329, United States.
3 Department of Chemistry, Emory University , 1515 Dickey Drive, Atlanta, Georgia 30322, United States ; Emory Institute for Drug Development, 954 Gatewood Road NE, Atlanta, Georgia 30329, United States.

PMID: 24936240 DOI: 10.1021/ml400183q

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.

Keywords

CXCR4 antagonists; CXCR4 receptor; HIV; Tetrahydroisoquinolines; WBC mobilization.

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