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Background:  Chemokine receptors, CXCR4 and CCR5, which are used as coreceptors by HIV-1, are considered attractive targets for possible intervention of HIV-1 infection. We previously reported KRH-1636 as a duodenally absorbable CXCR4 antagonist and X4 HIV-1 inhibitor. Our continuous efforts to find more effective CXCR4 inhibitors have recently allowed us to identify KRH-2731, an orally bioavailable CXCR4 antagonist.

Methods:  Anti-HIV-1 activity of KRH-2731 was assayed with various HIV-1 strains in activated PBMCs. Inhibition of chemokine binding and chemokine receptor-mediated Ca²⁺ signaling were determined using various chemokine receptor-expressing cells and their ligands. KRH-2731 was orally administered to hu-PBL-SCID mice and tested for its in vivo activity. Pharmacokinetic properties of KRH-2731 were determined in rats and dogs.

Results:  KRH-2731 efficiently inhibited the replication of all X4 and R5X4 HIV-1 strains tested (EC₅₀ of 1.0 to 4.2 nM), but did not inhibit that of R5 HIV-1 strains in activated PBMC. KRH-2731 specifically inhibited SDF-1alpha binding to CXCR4 and SDF-1-a-induced increase in the intracellular Ca²⁺ concentration of HOS/CXCR4 cells. The binding site of KRH-2731 was located in the second and/or third extracellular loops of CXCR4. KRH-2731 successfully suppressed X4 HIV-1 replication in hu-PBL-SCID mice when administered orally at a dose of 10 mg/kg. When KRH-2731 was administered orally to rats at a dose of 10 mg/kg, its bioavailability was 37%.

Conclusions:  KRH-2731 is an orally bioavailable CXCR4 antagonist with a potent and selective anti-X4 HIV-1 activity in both in vitro and in vivo, indicating a desirable additive to an anti-HIV-1 therapy.

Keywords: anti-HIV-1 drug; chemokine receptor antagonist; orally bioavailable