Steroid sulfatase inhibitors for the tropical treatment of skin disorders

Inhibition of steroid sulfatase (STS) activity in skin is a potential new treatment strategy for a number of skin disorders, including hirsutism, androgen-dependent alopecia, acne and psoriasis. In skin and its appendages, STS regulates the hydrolysis of dehydroepiandrosterone sulfate to dehydroepiandrosterone, a weak androgen, which can be converted to the biologically active androgens testosterone and 5 alpha-dihydrotestosterone by other steroidogenic enzymes also present in skin. A number of potent, irreversible STS inhibitors have been developed based around a core arylsulfamate ester motif, the active pharmacophore required for potent STS inhibition. Such inhibitors include AHBS and STX-64. Topical application of AHBS to the skin of mice or pigs resulted in almost complete inhibition of skin STS activity. Furthermore, when applied to the skin of Gottingen minipigs daily for 2 weeks, by day 10 AHBS had inhibited sebum production, a desired requisite for an antiacne drug. When applied topically to the skin of nude mice at 1.0 and 10.0 mg/kg STX-64 inhibited skin STS activity by > 90%, but it also inhibited liver STS activity. While preclinical studies have confirmed the ability of topically applied STS inhibitors to inhibit skin STS activity, further studies using preclinical models of skin disorders and clinical trials are needed to test their efficacy in treating skin disorders.