Chemistry:MK-386

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Short description: Chemical compound
MK-386
MK-386 structure.svg
Clinical data
Other namesL-733692; 4,7β-Dimethyl-4-aza-5α-cholestan-3-one[1]
Routes of
administration		By mouth
Drug class5α-Reductase inhibitor
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
FormulaC28H49NO
Molar mass415.706 g·mol−1
3D model (JSmol)

MK-386, also known as 4,7β-dimethyl-4-aza-5α-cholestan-3-one, is a synthetic, steroidal 5α-reductase inhibitor which was first reported in 1994 and was never marketed.[1][2] It is a 4-azasteroid and a potent and selective inhibitor of 5α-reductase type I 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.[2][3] 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.[4]

MK-386 has been found to decrease circulating concentrations of dihydrotestosterone (DHT) in men by 20 to 30%,[5] 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%.[6] In contrast to MK-386, the selective 5α-reductase type II inhibitor finasteride 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%.[7] Co-administration of MK-386 and finasteride was found to produce near-complete (~95%) suppression of circulating DHT levels.[8]

MK-386 has been found to significantly decrease concentrations of DHT in sebum, similarly to the selective 5α-reductase type II inhibitor finasteride.[9] 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%.[9] While finasteride decreases semen DHT levels by approximately 88%, MK-386 has been found to have no effect on levels of DHT in semen.[9] These findings are in accordance with the known tissue distribution of 5α-reductase isoforms.[10]

MK-386 was assessed in the treatment of acne but failed to separate from placebo in effectiveness and was significantly inferior to antibiotic therapy with minocycline.[11][12] In addition, the addition of MK-386 to minocycline failed to increase effectiveness relative to minocycline alone.[11][12] 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.[13][14]

References

  1. ↑ 1.0 1.1 "4,7 beta-Dimethyl-4-azacholestan-3-one (MK-386) and related 4-azasteroids as selective inhibitors of human type 1 5 alpha-reductase". Journal of Medicinal Chemistry 37 (23): 3871–3874. November 1994. doi:10.1021/jm00049a003. PMID 7966146. 
  2. ↑ 2.0 2.1 "MK386: a potent, selective inhibitor of the human type 1 5alpha-reductase". The Journal of Steroid Biochemistry and Molecular Biology 58 (4): 377–384. July 1996. doi:10.1016/0960-0760(96)00050-7. PMID 8903421. 
  3. ↑ "Inhibitors of 5-alpha-reductase". Current Pharmaceutical Design (Bentham Science Publishers) 2 (1): 59-84 (67). February 1996. doi:10.2174/1381612802666220920215559. https://books.google.com/books?id=IYn4Va7wtAoC&pg=PA67. 
  4. ↑ "Novel inhibitors of 5α-reductase". Expert Opinion on Therapeutic Patents 12 (2): 201–215. 2005. doi:10.1517/13543776.12.2.201. ISSN 1354-3776. 
  5. ↑ "Effect of MK-386, a novel inhibitor of type 1 5 alpha-reductase, alone and in combination with finasteride, on serum dihydrotestosterone concentrations in men". The Journal of Clinical Endocrinology and Metabolism 81 (8): 2942–2947. August 1996. doi:10.1210/jcem.81.8.8768856. PMID 8768856. 
  6. ↑ "Clinical biochemistry of dihydrotestosterone". Annals of Clinical Biochemistry 50 (Pt 2): 95–107. March 2013. doi:10.1258/acb.2012.012159. PMID 23431485. 
  7. ↑ "Anti-hormome Therapy: Principles of Endocrine Therapy of Cancer". Cancer. Springer Science & Business Media. 30 January 2007. pp. 49–. ISBN 978-3-540-33120-9. https://books.google.com/books?id=fdtDAAAAQBAJ&pg=PA49. 
  8. ↑ "Clinical use of 5alpha-reductase inhibitors". Testosterone: Action, Deficiency, Substitution. Cambridge University Press. 1 April 2004. pp. 586–. ISBN 978-1-139-45221-2. https://books.google.com/books?id=ZiZ7MWDqo5oC&pg=PA586. 
  9. ↑ 9.0 9.1 9.2 "MK-386, an inhibitor of 5alpha-reductase type 1, reduces dihydrotestosterone concentrations in serum and sebum without affecting dihydrotestosterone concentrations in semen". The Journal of Clinical Endocrinology and Metabolism 82 (5): 1373–1377. May 1997. doi:10.1210/jcem.82.5.3912. PMID 9141518. 
  10. ↑ "5 alpha-Reductase inhibitors". Drug Discovery and Design. Advances in Protein Chemistry (Academic Press) 56: 143–180 (172). 18 April 2001. doi:10.1016/s0065-3233(01)56005-2. ISBN 978-0-08-049338-1. PMID 11329853. https://books.google.com/books?id=aH6vjC-tXV8C&pg=PA172. 
  11. ↑ 11.0 11.1 "A systemic type I 5 alpha-reductase inhibitor is ineffective in the treatment of acne vulgaris". Journal of the American Academy of Dermatology 50 (3): 443–447. March 2004. doi:10.1016/j.jaad.2003.07.021. PMID 14988688. 
  12. ↑ 12.0 12.1 "The 5 alpha-reductase isozyme family: a review of basic biology and their role in human diseases". Advances in Urology 2012: 530121. 2012. doi:10.1155/2012/530121. PMID 22235201. 
  13. ↑ "Androgens and alopecia". Molecular and Cellular Endocrinology 198 (1–2): 89–95. December 2002. doi:10.1016/S0303-7207(02)00372-6. PMID 12573818. 
  14. ↑ "5α-Reductase Inhibitors in the Treatment of Androgenetic Alopecia". International Journal of Cosmetic Surgery and Aesthetic Dermatology 3 (2): 107–119. 2001. doi:10.1089/153082001753231036. ISSN 1530-8200. 



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