KRH-3955 hydrochloride is a CXCR4 antagonist with oral bioavailability. It effectively inhibits the binding of SDF-1α to CXCR4, exhibiting an IC 50 of 0.61 nM. Additionally, KRH-3955 hydrochloride displays high potency and selectivity as an inhibitor of X4 HIV-1, with an EC 50 ranging from 0.3 to 1.0 nM.

X4 HIV-1 (NL4.3):0.3-1.0 nM (EC50), SDF-1α-CXCR4:0.61 nM (IC50)

KRH-3955 inhibits the replication of NL4-3 in activated peripheral blood mononuclear cells (PBMCs) from eight different donors with the EC 50 ranging from 0.23 to 1.3 nM[1]. KRH-3955 inhibits the infection of CD4/CXCR4 cells by these recombinant drug-resistant viruses, including viruses resistant to PIs, NRTIs, or NNRTIs, multidrug-resistant viruses and T20-resistant viruses, with the IC 50 ranging from 0.4 to 0.8 nM[1]. KRH-3955 (10-100 nM) inhibits the SDF-1α-induced increase in the intracellular Ca 2+ concentration in a dose-dependent manner[1]. KRH-3955 (0.1-1000 nM) binding sites are located in a region composed of all three extracellular loops (ECLs) of CXCR4[1]. KRH-3955 (10 nM) has a strong binding affinity for CXCR4 and a slow dissociation rate[1]. KRH-3955 inhibits MAb 12G5 binding to CXCR4 mutants, with the IC 50 ranging from 0.5 to 14.1 nM[1].

KRH-3955 (10 mg/kg; a single p.o.) efficiently suppresses X4 HIV-1 infection in hu-PBL-SCID mice[1]. KRH-3955 (10 mg/kg; a single p.o.) exhibits moderate oral bioavailability (25.6%) and C max (86.3 ng/mL)[1]. KRH-3955 (10 mg/kg; a single i.v.) exhibits terminal elimination half-lives (99 h) due to high plasma clearance (3.9 liters/h/kg) combined with large volumes of distribution (374 liters/kg)[1]. Animal Model: C.B-17 SCID mice engrafted with human PBMCs and injected with infectious X4 HIV-1 (NL4-3)[1]Dosage: 10 mg/kg Administration: A single p.o. administration Result: Four of five mock-treated mice were infected whereas only one of five mice treated with KRH-3955 was infected. Animal Model: Male Sprague-Dawley rats[1]Dosage: 10 mg/kg (Pharmacokinetic Analysis) Administration: A single p.o. or i.v. administration Result: Well absorbed and the absolute oral bioavailability in rats was calculated to be 25.6%. The half time (T 1/2 ) of 99.0±13.1 h. Stable in human hepatic microsomes, and no significant inhibition of CYP450 liver enzymes by this compound was observed.