MK-386

MK-386
Clinical data
Other names	L-733692; 4,7β-Dimethyl-4-aza-5α-cholestan-3-one
Routes of; administration	By mouth
Drug class	5α-Reductase inhibitor
Identifiers
	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;
CAS Number	158493-17-5 ;
PubChem CID	9888107;
ChemSpider	154966;
UNII	JWDKP12EUC;
CompTox Dashboard (EPA)	DTXSID20935926 ;
Chemical and physical data
Formula	C28H49NO
Molar mass	415.706 g·mol−1
3D model (JSmol)	Interactive image;
	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;
	InChI InChI=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; Key: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.^[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

^ ^a ^b Bakshi RK, Patel GF, Rasmusson GH, Baginsky WF, Cimis G, Ellsworth K, et al. (November 1994). "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. doi:10.1021/jm00049a003. PMID 7966146.
^ ^a ^b Ellsworth K, Azzolina B, Baginsky W, Bull H, Chang B, Cimis G, et al. (July 1996). "MK386: a potent, selective inhibitor of the human type 1 5alpha-reductase". The Journal of Steroid Biochemistry and Molecular Biology. 58 (4): 377–384. doi:10.1016/0960-0760(96)00050-7. PMID 8903421. S2CID 54344877.
^ Frye SV (February 1996). "Inhibitors of 5-alpha-reductase". Current Pharmaceutical Design. 2 (1). Bentham Science Publishers: 59-84 (67). doi:10.2174/1381612802666220920215559. S2CID 252491829.
^ Machetti F, Guarna A (2005). "Novel inhibitors of 5α-reductase". Expert Opinion on Therapeutic Patents. 12 (2): 201–215. doi:10.1517/13543776.12.2.201. ISSN 1354-3776. S2CID 85073794.
^ Schwartz JI, Van Hecken A, De Schepper PJ, De Lepeleire I, Lasseter KC, Shamblen EC, et al. (August 1996). "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. doi:10.1210/jcem.81.8.8768856. PMID 8768856.
^ Marchetti PM, Barth JH (March 2013). "Clinical biochemistry of dihydrotestosterone". Annals of Clinical Biochemistry. 50 (Pt 2): 95–107. doi:10.1258/acb.2012.012159. PMID 23431485. S2CID 8325257.
^ Hoffman J, Sommer A (30 January 2007). "Anti-hormome Therapy: Principles of Endocrine Therapy of Cancer". In Bradbury R (ed.). Cancer. Springer Science & Business Media. pp. 49–. ISBN 978-3-540-33120-9.
^ Kaufman KD (1 April 2004). "Clinical use of 5alpha-reductase inhibitors". In Nieschlag E, Behre HM (eds.). Testosterone: Action, Deficiency, Substitution. Cambridge University Press. pp. 586–. ISBN 978-1-139-45221-2.
^ ^a ^b ^c Schwartz JI, Tanaka WK, Wang DZ, Ebel DL, Geissler LA, Dallob A, et al. (May 1997). "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. doi:10.1210/jcem.82.5.3912. PMID 9141518.
^ McConnell JD, Stoner E (18 April 2001). "5 alpha-Reductase inhibitors". Drug Discovery and Design. Advances in Protein Chemistry. 56. Academic Press: 143–180 (172). doi:10.1016/s0065-3233(01)56005-2. ISBN 978-0-08-049338-1. PMID 11329853.
^ ^a ^b Leyden J, Bergfeld W, Drake L, Dunlap F, Goldman MP, Gottlieb AB, et al. (March 2004). "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. doi:10.1016/j.jaad.2003.07.021. PMID 14988688.
^ ^a ^b Azzouni F, Godoy A, Li Y, Mohler J (2012). "The 5 alpha-reductase isozyme family: a review of basic biology and their role in human diseases". Advances in Urology. 2012: 530121. doi:10.1155/2012/530121. PMC 3253436. PMID 22235201.
^ Kaufman KD (December 2002). "Androgens and alopecia". Molecular and Cellular Endocrinology. 198 (1–2): 89–95. doi:10.1016/S0303-7207(02)00372-6. PMID 12573818. S2CID 2461147.
^ Kaufman KD (2001). "5α-Reductase Inhibitors in the Treatment of Androgenetic Alopecia". International Journal of Cosmetic Surgery and Aesthetic Dermatology. 3 (2): 107–119. doi:10.1089/153082001753231036. ISSN 1530-8200.

[pmid7966146-1] Bakshi RK, Patel GF, Rasmusson GH, Baginsky WF, Cimis G, Ellsworth K, et al. (November 1994). "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. doi:10.1021/jm00049a003. PMID 7966146.

[pmid8903421-2] Ellsworth K, Azzolina B, Baginsky W, Bull H, Chang B, Cimis G, et al. (July 1996). "MK386: a potent, selective inhibitor of the human type 1 5alpha-reductase". The Journal of Steroid Biochemistry and Molecular Biology. 58 (4): 377–384. doi:10.1016/0960-0760(96)00050-7. PMID 8903421. S2CID 54344877.

[Publishers1996-3] Frye SV (February 1996). "Inhibitors of 5-alpha-reductase". Current Pharmaceutical Design. 2 (1). Bentham Science Publishers: 59-84 (67). doi:10.2174/1381612802666220920215559. S2CID 252491829.

[MachettiGuarna2005-4] Machetti F, Guarna A (2005). "Novel inhibitors of 5α-reductase". Expert Opinion on Therapeutic Patents. 12 (2): 201–215. doi:10.1517/13543776.12.2.201. ISSN 1354-3776. S2CID 85073794.

[pmid8768856-5] Schwartz JI, Van Hecken A, De Schepper PJ, De Lepeleire I, Lasseter KC, Shamblen EC, et al. (August 1996). "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. doi:10.1210/jcem.81.8.8768856. PMID 8768856.

[pmid23431485-6] Marchetti PM, Barth JH (March 2013). "Clinical biochemistry of dihydrotestosterone". Annals of Clinical Biochemistry. 50 (Pt 2): 95–107. doi:10.1258/acb.2012.012159. PMID 23431485. S2CID 8325257.

[Bradbury2007-7] Hoffman J, Sommer A (30 January 2007). "Anti-hormome Therapy: Principles of Endocrine Therapy of Cancer". In Bradbury R (ed.). Cancer. Springer Science & Business Media. pp. 49–. ISBN 978-3-540-33120-9.

[NieschlagBehre2004-8] Kaufman KD (1 April 2004). "Clinical use of 5alpha-reductase inhibitors". In Nieschlag E, Behre HM (eds.). Testosterone: Action, Deficiency, Substitution. Cambridge University Press. pp. 586–. ISBN 978-1-139-45221-2.

[pmid9141518-9] Schwartz JI, Tanaka WK, Wang DZ, Ebel DL, Geissler LA, Dallob A, et al. (May 1997). "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. doi:10.1210/jcem.82.5.3912. PMID 9141518.

[AcademicPress2001-10] McConnell JD, Stoner E (18 April 2001). "5 alpha-Reductase inhibitors". Drug Discovery and Design. Advances in Protein Chemistry. 56. Academic Press: 143–180 (172). doi:10.1016/s0065-3233(01)56005-2. ISBN 978-0-08-049338-1. PMID 11329853.

[pmid14988688-11] Leyden J, Bergfeld W, Drake L, Dunlap F, Goldman MP, Gottlieb AB, et al. (March 2004). "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. doi:10.1016/j.jaad.2003.07.021. PMID 14988688.

[pmid22235201-12] Azzouni F, Godoy A, Li Y, Mohler J (2012). "The 5 alpha-reductase isozyme family: a review of basic biology and their role in human diseases". Advances in Urology. 2012: 530121. doi:10.1155/2012/530121. PMC 3253436. PMID 22235201.

[pmid12573818-13] Kaufman KD (December 2002). "Androgens and alopecia". Molecular and Cellular Endocrinology. 198 (1–2): 89–95. doi:10.1016/S0303-7207(02)00372-6. PMID 12573818. S2CID 2461147.

[Kaufman2001-14] Kaufman KD (2001). "5α-Reductase Inhibitors in the Treatment of Androgenetic Alopecia". International Journal of Cosmetic Surgery and Aesthetic Dermatology. 3 (2): 107–119. doi:10.1089/153082001753231036. ISSN 1530-8200.

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MK-386

References

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