Wikipedia

MK-4541

MK-4541 is a dual selective androgen receptor modulator (SARM) and 5α-reductase inhibitor (5α-RI) which has been of interest for the potential treatment of prostate cancer but has not been marketed at this time.[2][3][1][4][5][6] It is intended for use by mouth.[1]

MK-4541
Clinical data
Other namesMK4541
Routes of
administration		Oral[1]
Drug classSelective androgen receptor modulator; 5α-Reductase inhibitor[2]
Identifiers
  • 2,2,2-trifluoroethyl N-[(1S,3aS,3bS,5aR,9aR,9bS,11aS)-6,9a,11a-trimethyl-7-oxo-2,3,3a,3b,4,5,5a,9b,10,11-decahydro-1H-indeno[5,4-f]quinolin-1-yl]carbamate
CAS Number
PubChem CID
DrugBank
ChemSpider
Chemical and physical data
FormulaC22H31F3N2O3
Molar mass428.496 g·mol−1
3D model (JSmol)
  • C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@@H]2NC(=O)OCC(F)(F)F)CC[C@@H]4[C@@]3(C=CC(=O)N4C)C
  • InChI=1S/C22H31F3N2O3/c1-20-10-8-15-13(4-7-17-21(15,2)11-9-18(28)27(17)3)14(20)5-6-16(20)26-19(29)30-12-22(23,24)25/h9,11,13-17H,4-8,10,12H2,1-3H3,(H,26,29)/t13-,14-,15-,16-,17+,20-,21+/m0/s1
  • Key:OGBFNZPDLOPGEO-OCWMMRLVSA-N

The drug is a steroidal androgen receptor (AR) modulator with mixed agonistic (androgenic) and antagonistic (antiandrogenic) effects.[7][8][4][5][6] In preclinical research and animal studies, MK-4541 has been found to have androgenic or anabolic effects in muscle and bone, to strongly suppress testosterone levels (likely via androgenic antigonadotropic effects), and to have antiandrogenic effects in the prostate and in prostate cancer cells.[7][8][4][5][6] Structurally, it is specifically a 4-azasteroid derivative.[2]

MK-4541 was first described in the scientific literature by 2014.[5][6] It was identified by screening of 3,000 compounds that were manually designed and predicted to have SARM activity.[9][5] The drug was developed by Merck.[3] It might be being developed for potential medical use, but its developmental status has not been publicly disclosed.[3] In any case, MK-4541 is not known to have advanced past preclinical studies as of 2020.[1]

See also

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References

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  1. ^ a b c d Christiansen AR, Lipshultz LI, Hotaling JM, Pastuszak AW (March 2020). "Selective androgen receptor modulators: the future of androgen therapy?". Translational Andrology and Urology. 9 (Suppl 2): S135–S148. doi:10.21037/tau.2019.11.02. PMC 7108998. PMID 32257854.
  2. ^ a b c "MK-4541: Uses, Interactions, Mechanism of Action". DrugBank Online. 26 September 2022. Retrieved 22 October 2024.
  3. ^ a b c Fonseca GW, Dworatzek E, Ebner N, Von Haehling S (August 2020). "Selective androgen receptor modulators (SARMs) as pharmacological treatment for muscle wasting in ongoing clinical trials". Expert Opinion on Investigational Drugs. 29 (8): 881–891. doi:10.1080/13543784.2020.1777275. PMID 32476495.
  4. ^ a b c Lena A, Anker MS, Springer J (September 2020). "Muscle Wasting and Sarcopenia in Heart Failure-The Current State of Science". International Journal of Molecular Sciences. 21 (18): 6549. doi:10.3390/ijms21186549. PMC 7555939. PMID 32911600. MK-4541 [130], an androgen receptor agonist with 5α-reductase inhibitor function, exhibited anabolic effects and improvement of muscle function in castrated male mice.
  5. ^ a b c d e Schmidt A, Meissner RS, Gentile MA, Chisamore MJ, Opas EE, Scafonas A, et al. (September 2014). "Identification of an anabolic selective androgen receptor modulator that actively induces death of androgen-independent prostate cancer cells". The Journal of Steroid Biochemistry and Molecular Biology. 143: 29–39. doi:10.1016/j.jsbmb.2014.02.005. PMID 24565564.
  6. ^ a b c d Chisamore MJ, Gentile MA, Dillon GM, Baran M, Gambone C, Riley S, et al. (October 2016). "A novel selective androgen receptor modulator (SARM) MK-4541 exerts anti-androgenic activity in the prostate cancer xenograft R-3327G and anabolic activity on skeletal muscle mass & function in castrated mice". The Journal of Steroid Biochemistry and Molecular Biology. 163: 88–97. doi:10.1016/j.jsbmb.2016.04.007. PMID 27106747.
  7. ^ a b Birudukota N, Mudgal MM, Shanbhag V (December 2019). "Discovery and development of azasteroids as anticancer agents". Steroids. 152: 108505. doi:10.1016/j.steroids.2019.108505. PMID 31568765.
  8. ^ a b Solomon ZJ, Mirabal JR, Mazur DJ, Kohn TP, Lipshultz LI, Pastuszak AW (January 2019). "Selective Androgen Receptor Modulators: Current Knowledge and Clinical Applications". Sexual Medicine Reviews. 7 (1): 84–94. doi:10.1016/j.sxmr.2018.09.006. PMC 6326857. PMID 30503797. Likewise, work by Schmidt et al. focused on MK-4541, which induces Caspase-3 activity and apoptosis in androgen independent AR positive prostate cancer cell lines while sparing AR- and AR + non-prostate cancer cells.[25] Chisamore et al. also demonstrated that administration of MK-4541 resulted in a decrease in plasma testosterone levels, likely through AR-mediated negative feedback signaling through the hypothalamic-pituitary-gonadal axis.[13]
  9. ^ Li D, Zhou W, Pang J, Tang Q, Zhong B, Shen C, et al. (September 2019). "A magic drug target: Androgen receptor". Medicinal Research Reviews. 39 (5): 1485–1514. doi:10.1002/med.21558. PMID 30569509. In literatures, a group of nonsteroidal SARMs (eg, RAD140 [36],153 MK‐4541 [37],154 and BA321 [38] 155) have been reported. [...] MK‐4541 was screened out from 3000 manually designed SARMs by biological experiments established to distinguish AR antagonists in PCa therapy, and then further verified by its anabolic activity.152,156
 

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