Liarozole dihydrochloride

Product NameLiarozole dihydrochloride
CAS1883548-96-6
MFC17H14Cl2N4
MW345.23
EINECS
MOL File1883548-96-6.mol

Chemical Properties

storage temp.	room temp
solubility	Water: ≥ 50 mg/mL (131.00 mM); DMSO: 50 mg/mL (131.00 mM)
form	powder
color	white to beige
Water Solubility	H2O: 2mg/mL, clear
SMILES	ClC1=CC(C(C2=CC=C3N=CNC3=C2)N4C=CN=C4)=CC=C1

Safety Information

WGK Germany	WGK 3
Storage Class	13 - Non Combustible Solids

Usage And Synthesis

Uses

Liarozole (R75251) dihydrochloride is an imidazole derivative and orally active retinoic acid (RA) metabolism-blocking agent (RAMBA). Liarozole dihydrochloride inhibits the cytochrome P450 (CYP26)-dependent 4-hydroxylation of RA (IC50=7 μM), resulting in increased tissue levels of RA. Liarozole dihydrochloride shows antitumoral properties[1][2][3].

Biological Activity

Liarozole (R 75251, R75,251) is an orally active benzimidazole-based retinoic acid (RA) metabolism blocking agent (RAMBA) th at targets multiple P450 enzymes, including aromatase (CYP19), 17-hydroxylase/17,20-lyase (CYP17A1), 11-hydroxylase (CYP11B1), and RA 4-hydroxylase (CYP26). Liarozole is more effective than ketoconazole in vivo (plasma RA enhancement = 2.5 ng/mL vs. 1.3 ng/mL 2 hr after respective oral dosage of 40 mg/kg in rats) and, in contrast to ketoconazole, Liarozole does not significantly affect circulating adrenal androgen levels. Liarozole is shown to effectively suppress androgen-dependent tumor expansion of R3327G Dunning prostate adenocarcinoma xenografts in rats (by 66% and 81% with 80 and 120 mg/kg/day p.o., respectively) independent of its androgen biosynthesis inhibition.

in vivo

Liarozole dihydrochloride (5-20 mg/kg; p.o.) reverses the vaginal keratosis caused by estrogen stimulation^[5].
Liarozole dihydrochloride (40 mg/kg; p.o.) reduces tumor burden substantially^[6].

Animal Model:	Ovariectomized rats
Dosage:	5~20 mg/kg
Administration:	P.o.
Result:	Reversed the vaginal keratosis caused by estrogen stimulation.

Animal Model:	SCID mice
Dosage:	40 mg/kg
Administration:	P.o.
Result:	Inhibited tumor growth and survival.

IC 50

CYP26: 7 μM (IC₅₀)

storage

Desiccate at RT

References

[1] Kuijpers AL, et al. The effects of oral liarozole on epidermal proliferation and differentiation in severe plaque psoriasis are comparable with those of acitretin. Br J Dermatol. 1998;139(3):380-389. DOI:10.1046/j.1365-2133.1998.02399.x
[2] Lucker GP, et al. Oral treatment of ichthyosis by the cytochrome P-450 inhibitor liarozole. Br J Dermatol. 1997;136(1):71-75. PMID:9039298
[3] Wouters W, et al. Effects of liarozole, a new antitumoral compound, on retinoic acid-induced inhibition of cell growth and on retinoic acid metabolism in MCF-7 human breast cancer cells. Cancer Res. 1992;52(10):2841-2846. PMID:1581897
[4] Pignatello MA, et al. Liarozole markedly increases all trans-retinoic acid toxicity in mouse limb bud cell cultures: a model to explain the potency of the aromatic retinoid (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylenyl)-1-propenyl] benzoic acid. Toxicol Appl Pharmacol. 2002; 178(3):186-194. DOI:10.1006/taap.2001.9340
[5] Van Wauwe J, et al. Liarozole, an inhibitor of retinoic acid metabolism, exerts retinoid-mimetic effects in vivo. J Pharmacol Exp Ther. 1992;261(2):773-779. PMID:1374473
[6] Stearns ME, et al. Liarozole and 13-cis-retinoic acid anti-prostatic tumor activity [published correction appears in Cancer Res 1993 Dec 1;53(23):5831]. Cancer Res. 1993;53(13):3073-3077. PMID:8319215

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