6-[2-(adamantylidene)-hydroxybenzoxazole]-O-sulfamate, a steroid sulfatase inhibitor for the treatment of androgen- and estrogen-dependent diseases.
Steroid sulfatase (STS) offers a new target for the treatment of steroid hormone-dependent diseases, such as breast and prostate cancer and androgen-dependent skin diseases. We here characterize a novel non-estrogenic inhibitor of the enzyme, namely 6-[2-(adamantylidene)-hydroxybenzoxazole]-O-sulfamate (AHBS), with special attention to its potential use in the treatment of acne. The compound blocks STS activity in homogenates of human skin with IC(50)=16 nM. Following a single oral dose (5 mg/kg) in rats, the compound blocks STS in the skin by 95% at 8 h, followed by recovery of activity over 5 days. Following topical application to the skin, both in vitro and in vivo, AHBS passes through the stratum corneum leading to inhibition of STS activity in the dermal compartment with rapid onset and long duration. Topical application of AHBS to Göttingen minipigs for a period of 2 weeks does not induce symptoms of ichthyosis as seen in STS-deficient human subjects, but leads to a reduction of sebum secretion to the skin surface. Based on these data, clinical studies with AHBS in acne patients are warranted, in order to verify the hypothesis on the importance of the sulfatase pathway in androgen-dependent skin diseases.
Billich
Andreas
A
Novartis Institutes for BioMedical Research, Brunner Strasse 59, A-1235 Vienna, Austria. andreas.billich@pharma.novartis.com
Meingassner
Josef G
JG
Nussbaumer
Peter
P
Desrayaud
Sandrine
S
Lam
Charles
C
Winiski
Anthony
A
Schreiner
Erwin
E
D000042:Absorption; D000152:Acne Vulgaris / Q000188:drug therapy; D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D000279:Administration, Cutaneous; D000284:Administration, Oral; D000368:Aged; D000728:Androgens / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004967:Estrogens / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy*; D051381:Rats; D017208:Rats, Wistar; D012867:Skin / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013552:Swine
C496128:6-(2-(adamantylidene)-hydroxybenzoxazole)-O-sulfamate; D000728:Androgens; D004791:Enzyme Inhibitors; D004967:Estrogens; D043266:Steryl-Sulfatase; D000218:Adamantane