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Synthesis of Novel Tetrahydroisoquinoline CXCR4 Antagonists with Rigidified Side-Chains.

ABSTRACT: A structure-activity relationship study of potent TIQ15-derived CXCR4 antagonists is reported. In this investigation, the TIQ15 side-chain was constrained to improve its drug properties. The cyclohexylamino congener 15a was found to be a potent CXCR4 inhibitor (IC50 = 33 nM in CXCL12-mediated Ca2+ flux) with enhanced stability in liver microsomes and reduced inhibition of CYP450 (2D6). The improved CXCR4 antagonist 15a has potential therapeutic application as a single agent or combinatory anticancer therapy.

SUBMITTER: Jecs E

PROVIDER: S-EPMC5807867 | biostudies-other | 2018 Feb

REPOSITORIES: biostudies-other

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Synthesis of Novel Tetrahydroisoquinoline CXCR4 Antagonists with Rigidified Side-Chains.

Jecs Edgars E Miller Eric J EJ Wilson Robert J RJ Nguyen Huy H HH Tahirovic Yesim A YA Katzman Brook M BM Truax Valarie M VM Kim Michelle B MB Kuo Katie M KM Wang Tao T Sum Chi S CS Cvijic Mary E ME Schroeder Gretchen M GM Wilson Lawrence J LJ Liotta Dennis C DC

ACS medicinal chemistry letters 20171220 2

A structure-activity relationship study of potent TIQ15-derived CXCR4 antagonists is reported. In this investigation, the TIQ15 side-chain was constrained to improve its drug properties. The cyclohexylamino congener 15a was found to be a potent CXCR4 inhibitor (IC50 = 33 nM in CXCL12-mediated Ca2+ flux) with enhanced stability in liver microsomes and reduced inhibition of CYP450 (2D6). The improved CXCR4 antagonist 15a has potential therapeutic application as ...[more]

PMID: 29456793

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