Uses
Talarozole is a retinoic acid metabolism blocking agent (RAMBA) that can be used for treating dermatalogical diseases such as psoriasis and acne.
Definition
ChEBI: N-{4-[2-ethyl-1-(1,2,4-triazol-1-yl)butyl]phenyl}-1,3-benzothiazol-2-amine is a member of the class of benzothiazoles that is 2-amino-1,3-benzothiazole in which one of the amino hydrogens is replaced by a 4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl group. It is a member of triazoles, a member of benzothiazoles, an aromatic amine and a secondary amino compound.
Biological Activity
talarozole is a selective inhibitor of cytochrome p450 with an ic50 at 4 nm [1].cytochrome p450 is concerned with oxidative metabolism of many organic chemicals of diverse structure,both in exogenous and endogenous environment. cytochrome p450 are notable both for the diversity of reactions that they catalyze and the range of chemically dissimilar substrates upon which they act.talarozole is a potent and selective inhibitor of cytochrome p450 26-mediated breakdown of endogenous all-trans-retinoic acid for the treatment of psoriasis and acne. talarozole treatment increased the mrna expression of crabp2, krt4, cyp26a1 and cyp26b1 dose, meanwhile, compared with vehicle-treated skin, decreased the expression of krt2 and il-1α. there was no mrna change in retinol-metabolizing enzymes. no induction of epidermal thickness or overt skin inflammation in talarozole-treated skin. immunofluorescence analysis substantiated an upregulation of krt4 protein, however, there were no upregulation of cyp26b1 and cyp26a1 expression was found.[1, 2]there were 0.1% of the dose found in the skin itself after 12-24 h. the results of distribution of talarozole within the skin show that 80% was located in the epidermis, meanwhile, the remaining 20% was detected in the dermis. [3]
in vivo
A maximum 84% inhibition of CYP26 activity at 0.5 hours post-dose is predicted based on Talarozole (TLZ) Cmax of 80 nM and a Ki of 1 nM following a single dose of Talarozole. Due to the short Talarozole half-life (2.2 hrs) CYP26 activity is predicted to return to 100% by 12 hours. In agreement with the predictions, atRA concentrations are increased by 82, 63 and 60% at 4 hours post-dose in the serum, liver and testes, respectively, and concentrations returned to baseline by 24 hours. Following multiple doses of Talarozole, liver CYP26 mRNA and activity are increased suggesting autoinduction of CYP26 due to increased atRA concentrations. In agreement, atRA concentrations are elevated in serum and liver at all timepoints measured. This increase in atRA concentrations is associated with increased mRNA of the mitochondrial biogenesis markers PGC-1β and NRF-1 in comparison to control mice[3].
References
[1] pavez loriè e, cools m, borgers m, topical treatment with cyp26 inhibitor talarozole (r115866) dose dependently alters the expression of retinoid-regulated genes in normal human epidermis. the british journal of dermatology,2009,160(1):26-36.
[2] geria an, scheinfeld ns. talarozole, a selective inhibitor of p450-mediated all-trans retinoic acid for the treatment of psoriasis and acne. current opinion in investigational drugs,2008 ,9(11):1228-1237.
[3] baert b, de spiegeleer b. local skin pharmacokinetics of talarozole, a new retinoic acid metabolism-blocking agent. skin pharmacol physiol,2011,24(3):151-159
