Discovery of Novel Small Molecule Orally Bioavailable C−X−C Chemokine Receptor 4 Antagonists That Are Potent Inhibitors of T-Tropic (X4) HIV-1 Replication

TLDR

The study aimed to develop orally bioavailable CXCR4 antagonists that inhibit T‑tropic HIV‑1 replication. The authors performed a structure‑activity relationship study using X4 HIV‑1 NL4.3 replication inhibition in MT‑4 cells. Lead optimization yielded AMD070, a potent CXCR4 antagonist (IC50 13 nM) that inhibited T‑tropic HIV‑1 replication (IC50 2 nM in MT‑4 cells, 26 nM in PBMCs), was noncytotoxic up to 23 µM, and displayed good oral bioavailability in rats and dogs, representing the first orally bioavailable CXCR4 antagonist for HIV‑1 treatment.

Abstract

The redesign of azamacrocyclic CXCR4 chemokine receptor antagonists resulted in the discovery of novel, small molecule, orally bioavailable compounds that retained T-tropic (CXCR4 using, X4) anti-HIV-1 activity. A structure−activity relationship (SAR) was determined on the basis of the inhibition of replication of X4 HIV-1 NL4.3 in MT-4 cells. As a result of lead optimization, we identified (S)-N′-((1H-benzo[d]imidazol-2-yl)methyl)-N′-(5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine (AMD070) 2 as a potent and selective antagonist of CXCR4 with an IC50 value of 13 nM in a CXCR4 125I-SDF inhibition binding assay. Compound 2 inhibited the replication of T-tropic HIV-1 (NL4.3 strain) in MT-4 cells and PBMCs with an IC50 of 2 and 26 nM, respectively, while remaining noncytotoxic to cells at concentrations exceeding 23 μM. The pharmacokinetics of 2 was evaluated in rat and dog, and good oral bioavailability was observed in both species. This compound represents the first small molecule orally bioavailable CXCR4 antagonist that was developed for the treatment of HIV-1 infection.