MK386 - A POTENT, SELECTIVE INHIBITOR OF THE HUMAN TYPE-1 5-ALPHA-REDUCTASE

Steroid 5 alpha-reductase is required for the conversion of testostero ne to dihydrotestosterone. Localization of type 1 5 alpha-reductase in the sebaceous gland of skin offers the possibility for selective inhi bition of this isozyme as a treatment for acne. The goals of these stu dies are to demonstrate the mechanism of inhibition of MK386 and its s electivity for type 1 5 alpha-reductase. The apparent potency of MK386 differed depending on the source of the enzyme (i.e. recombinant vs. native), yet selectivity for type 1 Scr-reductase was unchanged. Our r esults indicate that the apparent potency of MK386 is modulated by the membrane concentration of the assay. These results suggest that MK386 has a high affinity for the Lipid-rich membrane environment of 5 alph a-reductase. MK386 was also found to be a slow binding inhibitor of ty pe 1 Scr-reductase. However, the cause of this time-dependent inhibiti on is unrelated to partitioning of the inhibitor into the membrane bec ause similar studies with type 2 5 alpha-reductase indicate that MK386 is a reversible, competitive inhibitor. A number of counterscreens we re developed to demonstrate that MK386 is a poor inhibitor of other st eroid metabolizing enzymes. Copyright (C) 1996 Elsevier Science Ltd.