MK-386, also known as 4,7β-dimethyl-4-aza-5α-cholestan-3-one, is a
synthetic Synthetic things are composed of multiple parts, often with the implication that they are artificial. In particular, 'synthetic' may refer to:
Science
* Synthetic chemical or compound, produced by the process of chemical synthesis
* Synthetic o ...
,
steroid
A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...
al
5α-reductase inhibitor
5α-Reductases, also known as 3-oxo-5α-steroid 4-dehydrogenases, are enzymes involved in steroid metabolism. They participate in three metabolic pathways: bile acid biosynthesis, androgen and estrogen metabolism. There are three isozymes of ...
which was first reported in 1994 and was never marketed.
It is a
4-azasteroid and a
potent and
selective inhibitor
Inhibitor or inhibition may refer to:
In biology
* Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity
* Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotra ...
of
5α-reductase
5α-Reductases, also known as 3-oxo-5α-steroid 4-dehydrogenases, are enzymes involved in steroid metabolism. They participate in three metabolic pathways: bile acid biosynthesis, androgen and estrogen metabolism. There are three isozymes of ...
type I Type 1 or Type I or ''variant'', may refer to:
Health
*Diabetes mellitus type 1 (also known as "Type 1 Diabetes"), insulin-dependent diabetes
* Type I female genital mutilation
* Type 1 personality
*Type I hypersensitivity (or immediate hypersensit ...
and shows high selectivity for inhibition of human 5α-reductase type I over 5α-reductase
type II, with
IC50 values of 0.9 nM and 154 nM, respectively.
The drug was under investigation for potential treatment of
androgen-dependent conditions such as
acne and
pattern hair loss (androgenic alopecia or baldness), but was discontinued in early
clinical trials due to observations of
hepatotoxicity such as
elevated liver enzymes
In medicine, the presence of elevated transaminases, commonly the transaminases alanine transaminase (ALT) and aspartate transaminase (AST), may be an indicator of liver dysfunction. Other terms include transaminasemia, transaminitis, and elevated ...
.
MK-386 has been found to decrease circulating concentrations of
dihydrotestosterone (DHT) in men by 20 to 30%,
which is in accordance with the fact that 5α-reductase
type II is responsible for 70 to 80% of DHT production while 5α-reductase type I is responsible for 20 to 30%.
In contrast to MK-386, the selective 5α-reductase type II inhibitor
finasteride
Finasteride, sold under the brand names Proscar and Propecia among others, is a medication used to treat hair loss and benign prostatic hyperplasia (BPH) in men. It can also be used to treat excessive hair growth in women and as a part of horm ...
has been found to decrease DHT levels by about 70%, while the non-selective 5α-reductase inhibitor
dutasteride decreases DHT levels by up to 98%.
Co-administration of MK-386 and finasteride was found to produce near-complete (~95%) suppression of circulating DHT levels.
MK-386 has been found to significantly decrease concentrations of DHT in
sebum, similarly to the selective 5α-reductase type II inhibitor finasteride.
However, whereas finasteride results in only a modest reduction in sebum DHT levels of 15%, MK-386 has been found to produce a significantly greater reduction of 55%.
While finasteride decreases
semen DHT levels by approximately 88%, MK-386 has been found to have no effect on levels of DHT in semen.
These findings are in accordance with the known tissue distribution of 5α-reductase isoforms.
MK-386 was assessed in the treatment of acne but failed to separate from
placebo in effectiveness and was significantly inferior to
antibiotic
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...
therapy with
minocycline.
In addition, the addition of MK-386 to minocycline failed to increase effectiveness relative to minocycline alone.
A study of MK-386 treatment for one year in stumptail macaques found that the drug failed to increase scalp hair weight in a model of androgenic alopecia, in contrast to finasteride.
References
{{Reflist, 2
5α-Reductase_inhibitors
Abandoned drugs
Cholestanes