MK-386
{{Short description|Chemical compound}}
{{Drugbox
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| IUPAC_name = (1R,3aS,3bS,4S,5aR,9aR,9bS,11aR)-4,6,9a,11a-Tetramethyl-1-[(2R)-6-methylheptan-2-yl]-2,3,3a,3b,4,5,5a,8,9,9b,10,11-dodecahydro-1H-indeno[5,4-f]quinolin-7-one
| image = MK-386 structure.svg
| width = 250px
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| routes_of_administration = By mouth
| class = 5α-Reductase inhibitor
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| CAS_number = 158493-17-5
| CAS_number_Ref = {{cascite|correct|CAS}}
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = JWDKP12EUC
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| PubChem = 9888107
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| ChemSpiderID = 154966
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| synonyms = L-733692; 4,7β-Dimethyl-4-aza-5α-cholestan-3-one
| C=28 | H=49 | N=1 | O=1
| SMILES = C[C@H]1C[C@@H]2[C@](CCC(=O)N2C)([C@@H]3[C@@H]1[C@@H]4CC[C@@H]([C@]4(CC3)C)[C@H](C)CCCC(C)C)C
| StdInChI_Ref =
| StdInChI = 1S/C28H49NO/c1-18(2)9-8-10-19(3)21-11-12-22-26-20(4)17-24-28(6,16-14-25(30)29(24)7)23(26)13-15-27(21,22)5/h18-24,26H,8-17H2,1-7H3/t19-,20+,21-,22+,23+,24-,26+,27-,28-/m1/s1
| StdInChIKey_Ref =
| StdInChIKey = XUTZDXHKQDPUMA-MVJJLJOTSA-N
}}
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.{{cite journal | vauthors = Bakshi RK, Patel GF, Rasmusson GH, Baginsky WF, Cimis G, Ellsworth K, Chang B, Bull H, Tolman RL, Harris GS | display-authors = 6 | title = 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 = Journal of Medicinal Chemistry | volume = 37 | issue = 23 | pages = 3871–3874 | date = November 1994 | pmid = 7966146 | doi = 10.1021/jm00049a003 }}{{cite journal | vauthors = Ellsworth K, Azzolina B, Baginsky W, Bull H, Chang B, Cimis G, Mitra S, Toney J, Bakshi RK, Rasmusson GR, Tolman RL, Harris GS | display-authors = 6 | title = MK386: a potent, selective inhibitor of the human type 1 5alpha-reductase | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 58 | issue = 4 | pages = 377–384 | date = July 1996 | pmid = 8903421 | doi = 10.1016/0960-0760(96)00050-7 | s2cid = 54344877 }} 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.{{cite journal | vauthors = Frye SV | title = Inhibitors of 5-alpha-reductase |journal = Current Pharmaceutical Design | volume = 2 | issue =1 |url= https://books.google.com/books?id=IYn4Va7wtAoC&pg=PA67|date=February 1996|publisher=Bentham Science Publishers|pages= 59-84 (67) | doi = 10.2174/1381612802666220920215559 | s2cid = 252491829 }} 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.{{cite journal| vauthors = Machetti F, Guarna A |title=Novel inhibitors of 5α-reductase|journal=Expert Opinion on Therapeutic Patents|volume=12|issue=2|year=2005|pages=201–215|issn=1354-3776|doi=10.1517/13543776.12.2.201|s2cid=85073794}}
MK-386 has been found to decrease circulating concentrations of dihydrotestosterone (DHT) in men by 20 to 30%,{{cite journal | vauthors = Schwartz JI, Van Hecken A, De Schepper PJ, De Lepeleire I, Lasseter KC, Shamblen EC, Winchell GA, Constanzer ML, Chavez CM, Wang DZ, Ebel DL, Justice SJ, Gertz BJ | display-authors = 6 | title = 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 | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 81 | issue = 8 | pages = 2942–2947 | date = August 1996 | pmid = 8768856 | doi = 10.1210/jcem.81.8.8768856 | doi-access = free }} 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%.{{cite journal | vauthors = Marchetti PM, Barth JH | title = Clinical biochemistry of dihydrotestosterone | journal = Annals of Clinical Biochemistry | volume = 50 | issue = Pt 2 | pages = 95–107 | date = March 2013 | pmid = 23431485 | doi = 10.1258/acb.2012.012159 | s2cid = 8325257 | doi-access = free }} 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%.{{cite book| vauthors = Hoffman J, Sommer A | chapter = Anti-hormome Therapy: Principles of Endocrine Therapy of Cancer | veditors = Bradbury R |title=Cancer| chapter-url=https://books.google.com/books?id=fdtDAAAAQBAJ&pg=PA49|date=30 January 2007|publisher=Springer Science & Business Media |isbn=978-3-540-33120-9|pages=49–}} Co-administration of MK-386 and finasteride was found to produce near-complete (~95%) suppression of circulating DHT levels.{{cite book| vauthors = Kaufman KD | chapter = Clinical use of 5alpha-reductase inhibitors | veditors = Nieschlag E, Behre HM |title=Testosterone: Action, Deficiency, Substitution| chapter-url = https://books.google.com/books?id=ZiZ7MWDqo5oC&pg=PA586|date=1 April 2004|publisher=Cambridge University Press|isbn=978-1-139-45221-2|pages=586–}}
MK-386 has been found to significantly decrease concentrations of DHT in sebum, similarly to the selective 5α-reductase type II inhibitor finasteride.{{cite journal | vauthors = Schwartz JI, Tanaka WK, Wang DZ, Ebel DL, Geissler LA, Dallob A, Hafkin B, Gertz BJ | display-authors = 6 | title = MK-386, an inhibitor of 5alpha-reductase type 1, reduces dihydrotestosterone concentrations in serum and sebum without affecting dihydrotestosterone concentrations in semen | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 82 | issue = 5 | pages = 1373–1377 | date = May 1997 | pmid = 9141518 | doi = 10.1210/jcem.82.5.3912 | doi-access = free }} 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.{{cite journal | vauthors = McConnell JD, Stoner E | title = 5 alpha-Reductase inhibitors | journal = Drug Discovery and Design | series = Advances in Protein Chemistry | volume = 56 | pages = 143–180 (172) | date = 18 April 2001 | pmid = 11329853 | url = https://books.google.com/books?id=aH6vjC-tXV8C&pg=PA172 | publisher = Academic Press | doi = 10.1016/s0065-3233(01)56005-2 | isbn = 978-0-08-049338-1 }}
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.{{cite journal | vauthors = Leyden J, Bergfeld W, Drake L, Dunlap F, Goldman MP, Gottlieb AB, Heffernan MP, Hickman JG, Hordinsky M, Jarrett M, Kang S, Lucky A, Peck G, Phillips T, Rapaport M, Roberts J, Savin R, Sawaya ME, Shalita A, Shavin J, Shaw JC, Stein L, Stewart D, Strauss J, Swinehart J, Swinyer L, Thiboutot D, Washenik K, Weinstein G, Whiting D, Pappas F, Sanchez M, Terranella L, Waldstreicher J | display-authors = 6 | title = A systemic type I 5 alpha-reductase inhibitor is ineffective in the treatment of acne vulgaris | journal = Journal of the American Academy of Dermatology | volume = 50 | issue = 3 | pages = 443–447 | date = March 2004 | pmid = 14988688 | doi = 10.1016/j.jaad.2003.07.021 }}{{cite journal | vauthors = Azzouni F, Godoy A, Li Y, Mohler J | title = The 5 alpha-reductase isozyme family: a review of basic biology and their role in human diseases | journal = Advances in Urology | volume = 2012 | pages = 530121 | year = 2012 | pmid = 22235201 | pmc = 3253436 | doi = 10.1155/2012/530121 | doi-access = free }} 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.{{cite journal | vauthors = Kaufman KD | title = Androgens and alopecia | journal = Molecular and Cellular Endocrinology | volume = 198 | issue = 1–2 | pages = 89–95 | date = December 2002 | pmid = 12573818 | doi = 10.1016/S0303-7207(02)00372-6 | s2cid = 2461147 }}{{cite journal| vauthors = Kaufman KD |title=5α-Reductase Inhibitors in the Treatment of Androgenetic Alopecia|journal=International Journal of Cosmetic Surgery and Aesthetic Dermatology|volume=3|issue=2|year=2001|pages=107–119|issn=1530-8200|doi=10.1089/153082001753231036}}