KRH-3955 hydrochloride

Category	Human immunodeficiency Virus (HIV)
CAS	2253744-59-9
Description	KRH-3955 hydrochloride is an orally bioavailable CXCR4 antagonist, and a highly potent and selective inhibitor of X4 HIV-1, with an EC50 of 0.3-1.0 nM. It inhibits the binding of CXCR4 to SDF-1α with an IC50 of 0.61 nM.

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Product Information

Synonyms	N1-[[4-[[(1H-Imidazol-2-ylmethyl)[(1-methyl-1H-imidazol-2-yl)methyl]amino]methyl]phenyl]methyl]-N1-methyl-N4,N4-dipropyl-1,4-butanediamine trihydrochloride; N-[4-({(1H-Imidazol-2-ylmethyl)[(1-methyl-1H-imidazol-2-yl)methyl]amino}methyl)benzyl]-N-methyl-N',N'-dipropyl-1,4-butanediamine trihydrochloride
IUPAC Name	N-[[4-[[1H-imidazol-2-ylmethyl-[(1-methylimidazol-2-yl)methyl]amino]methyl]phenyl]methyl]-N-methyl-N',N'-dipropylbutane-1,4-diamine;trihydrochloride
Molecular Weight	589.09
Molecular Formula	C28H48Cl3N7
Canonical SMILES	CCCN(CCC)CCCCN(C)CC1=CC=C(C=C1)CN(CC2=NC=CN2)CC3=NC=CN3C.Cl.Cl.Cl
InChI	InChI=1S/C28H45N7.3ClH/c1-5-16-34(17-6-2)19-8-7-18-32(3)21-25-9-11-26(12-10-25)22-35(23-27-29-13-14-30-27)24-28-31-15-20-33(28)4;;;/h9-15,20H,5-8,16-19,21-24H2,1-4H3,(H,29,30);3*1H
InChIKey	KLPOLRXJKIOFIQ-UHFFFAOYSA-N
Purity	≥95%
Solubility	In vitro: 10 mM in DMSO
Appearance	Solid powder
Storage	Store at -20°C
In Vitro	KRH-3955 inhibits the replication of NL4-3 in activated peripheral blood mononuclear cells (PBMCs) from eight different donors with the EC50 ranging from 0.23 to 1.3 nM. 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 IC50 ranging from 0.4 to 0.8 nM. KRH-3955 (10-100 nM) inhibits the SDF-1α-induced increase in the intracellular Ca2+ concentration in a dose-dependent manner. KRH-3955 (0.1-1000 nM) binding sites are located in a region composed of all three extracellular loops (ECLs) of CXCR4. KRH-3955 (10 nM) has a strong binding affinity for CXCR4 and a slow dissociation rate. KRH-3955 inhibits MAb 12G5 binding to CXCR4 mutants, with the IC50 ranging from 0.5 to 14.1 nM.
In Vivo	KRH-3955 (10 mg/kg; a single p.o.) efficiently suppresses X4 HIV-1 infection in hu-PBL-SCID mice. KRH-3955 (10 mg/kg; a single p.o.) exhibits moderate oral bioavailability (25.6%) and Cmax (86.3 ng/mL). 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).
Target	X4 HIV-1NL4-3: 0.3-1.0 nM (EC50) SDF-1α-CXCR4: 0.61 nM (IC50)