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A novel series of CXCR4 antagonists with piperidinyl and piperazinyl alkylamine side chains designed as butyl amine replacements are described. Several of these compounds showed similar activity to the parent compound TIQ-15 ( 5 ) in a SDF-1 induced calcium flux assay. Preliminary structure-activity relationship investigations led us to identify a series containing N -propyl piperazine side chain analogs exemplified by 16 with improved off-target effects as measured in a muscarinic acetylcholine receptor (mAChR) calcium flux assay and in a limited drug safety panel screen. Further efforts to explore SAR and optimize drug properties led to the identification of the N '-ethyl- N -propyl-piperazine tetrahydroisoquinoline derivative 44 and the N -propyl-piperazine benzimidazole compound 37 , which gave the best overall profiles with no mAChR or CYP450 inhibition, good permeability in PAMPA assays, and metabolic stability in human liver microsomes., Competing Interests: The authors declare the following competing financial interest(s): D.C.L. is the principle investigator on a research grant from Bristol-Myers Squibb Research and Development to Emory University. D.C.L., L.J.W., Y.A.T., E.J.M., E.J., H.H.N., R.J.W., V.T.T., and M.B.K. are coinventors on Emory-owned Intellectual Property that includes CXCR4 antagonists.

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 (IC 50 = 33 nM in CXCL12-mediated Ca 2+ 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., Competing Interests: The authors declare the following competing financial interest(s): D.C.L. is the principle investigator on a research grant from Bristol-Myers Squibb Research and Development to Emory University. D.C.L., L.J.W., E.J.M., E.J., H.H.N., Y.A.T., R.J.W., V.T.T., and M.B.K. are co-inventors on Emory-owned Intellectual Property that includes CXCR4 antagonists.