Jump to content

MK-0773: Difference between revisions

Add links
From Wikipedia, the free encyclopedia
Browse history interactively
← Previous edit
Content deleted Content added
VisualWikitext
No edit summary
OAbot (talk | contribs)
Bots
427,513 edits
m Open access bot: doi updated in citation with #oabot.
 
(24 intermediate revisions by 16 users not shown)
Line 1: Line 1:
{{short description|Chemical compound}}
{{Use dmy dates|date=April 2017}}
{{Drugbox
{{Drugbox
| Verifiedfields =
| Verifiedfields =
| Watchedfields =
| Watchedfields =
| verifiedrevid =
| verifiedrevid =
| IUPAC_name = (1S,3aS,3bS,5aR,9aS,9bS,11aS)-8-fluoro-N-(1H-imidazo[4,5-b]pyridin-2-ylmethyl)-6,9a,11a-trimethyl-7-oxo-2,3,3a,3b,4,5,5a,9b,10,11-decahydro-1H-indeno[5,4-f]quinoline-1-carboxamide
| IUPAC_name = (1''S'',3a''S'',3b''S'',5a''R'',9a''S'',9b''S'',11a''S'')-8-Fluoro-''N''-(1''H''-imidazo[4,5-b]pyridin-2-ylmethyl)-6,9a,11a-trimethyl-7-oxo-2,3,3a,3b,4,5,5a,9b,10,11-decahydro-1''H''-indeno[5,4-f]quinoline-1-carboxamide
| image =
| image = MK-0773.svg
| width =
| width = 250px


<!--Clinical data-->
<!--Clinical data-->
| tradename =
| tradename =
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = <!-- A / B / C / D / X -->
| pregnancy_US = <!-- A / B / C / D / X -->
| pregnancy_category =
| pregnancy_category =
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
Line 17: Line 19:
| legal_US =
| legal_US =
| legal_status =
| legal_status =
| routes_of_administration = [[Oral administration|Oral]]
| routes_of_administration = [[Oral administration|By mouth]]


<!--Pharmacokinetic data-->
<!--Pharmacokinetic data-->
Line 42: Line 44:
| KEGG =
| KEGG =
| ChEBI =
| ChEBI =
| ChEMBL =
| ChEMBL =
⚫
| synonyms = PF-05314882; N-(3''H''-Imidazo(4,5-b)pyridin-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide


<!--Chemical data-->
<!--Chemical data-->
| C=27 | H=34 | F=1 | N=5 | O=2
| C=27 | H=34 | F=1 | N=5 | O=2
| molecular_weight = 479.6 g/mol
| SMILES = C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@@H]2C(=O)NCC4=NC5=C(N4)C=CC=N5)CC[C@@H]6[C@@]3(C=C(C(=O)N6C)F)C
| SMILES = C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@@H]2C(=O)NCC4=NC5=C(N4)C=CC=N5)CC[C@@H]6[C@@]3(C=C(C(=O)N6C)F)C
| StdInChI_Ref =
| StdInChI_Ref =
Line 52: Line 54:
| StdInChIKey_Ref =
| StdInChIKey_Ref =
| StdInChIKey = GBEUKTWTUSPHEE-JWJWXJQQSA-N
| StdInChIKey = GBEUKTWTUSPHEE-JWJWXJQQSA-N
⚫
| synonyms = PF-05314882; N-(3''H''-Imidazo(4,5-b)pyridin-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide
}}
}}


'''MK-0773''', also known as '''PF-05314882''', is a [[steroid]]al, [[oral administration|orally active]] [[selective androgen receptor modulator]] (SARM) that was under development by [[Merck & Co.|Merck]] and [[GTx Incorporated|GTx]] for the treatment of [[sarcopenia]] (loss of [[muscle]] mass) in women and men.<ref name="pmid20356837">{{cite journal | vauthors = Schmidt A, Kimmel DB, Bai C, Scafonas A, Rutledge S, Vogel RL, McElwee-Witmer S, Chen F, Nantermet PV, Kasparcova V, Leu CT, Zhang HZ, Duggan ME, Gentile MA, Hodor P, Pennypacker B, Masarachia P, Opas EE, Adamski SA, Cusick TE, Wang J, Mitchell HJ, Kim Y, Prueksaritanont T, Perkins JJ, Meissner RS, Hartman GD, Freedman LP, Harada S, Ray WJ | title = Discovery of the selective androgen receptor modulator MK-0773 using a rational development strategy based on differential transcriptional requirements for androgenic anabolism versus reproductive physiology | journal = J. Biol. Chem. | volume = 285 | issue = 22 | pages = 17054–64 | year = 2010 | pmid = 20356837 | pmc = 2878020 | doi = 10.1074/jbc.M109.099002 | url = | issn = }}</ref><ref name="Ph.D.2013">{{cite book|author=David E. Newton Ph.D.|title=Steroids and Doping in Sports: A Reference Handbook: A Reference Handbook|url=https://books.google.com/books?id=tAtIAgAAQBAJ&pg=PA85|date=26 November 2013|publisher=ABC-CLIO|isbn=978-1-61069-314-1|pages=85–}}</ref><ref name="AdisInsight">http://webcache.googleusercontent.com/search?q=cache:kMshfiI-UnAJ:adisinsight.springer.com/drugs/800024550+&cd=1&hl=en&ct=clnk&gl=us</ref> Clinical trials for sarcopenia began in late 2007 but the collaboration between Merck and GTx ended in early 2010 and GTx terminated development of MK-0773 shortly thereafter.<ref name="Ph.D.2013" />
'''MK-0773''', also known as '''PF-05314882''', is a [[steroid]]al, [[oral administration|orally active]] [[selective androgen receptor modulator]] (SARM) that was under development by [[Merck & Co.|Merck]] and [[GTx Incorporated|GTx]] for the treatment of [[sarcopenia]] (loss of [[muscle]] mass) in women and men.<ref name="pmid20356837">{{cite journal | vauthors = Schmidt A, Kimmel DB, Bai C, Scafonas A, Rutledge S, Vogel RL, McElwee-Witmer S, Chen F, Nantermet PV, Kasparcova V, Leu CT, Zhang HZ, Duggan ME, Gentile MA, Hodor P, Pennypacker B, Masarachia P, Opas EE, Adamski SA, Cusick TE, Wang J, Mitchell HJ, Kim Y, Prueksaritanont T, Perkins JJ, Meissner RS, Hartman GD, Freedman LP, Harada S, Ray WJ | display-authors = 6 | title = Discovery of the selective androgen receptor modulator MK-0773 using a rational development strategy based on differential transcriptional requirements for androgenic anabolism versus reproductive physiology | journal = The Journal of Biological Chemistry | volume = 285 | issue = 22 | pages = 17054–17064 | date = May 2010 | pmid = 20356837 | pmc = 2878020 | doi = 10.1074/jbc.M109.099002 | doi-access = free }}</ref><ref name="Ph.D.2013">{{cite book| vauthors = Newton DE | chapter = Problems, Controversies, and Solutions|title=Steroids and Doping in Sports: A Reference Handbook: A Reference Handbook| chapter-url = https://books.google.com/books?id=tAtIAgAAQBAJ&pg=PA85|date=26 November 2013|publisher=ABC-CLIO|isbn=978-1-61069-314-1|pages=85–}}</ref><ref name="AdisInsight">{{cite web | title = MK 0773 | url = https://adisinsight.springer.com/drugs/800024550 | work = AdisInsight | publisher = Springer Nature Switzerland AG }}</ref> Clinical trials for sarcopenia began in late 2007 but the collaboration between Merck and GTx ended in early 2010 and GTx terminated development of MK-0773 shortly thereafter.<ref name="Ph.D.2013" /> MK-0773 was developed as a more advanced version of the related compound [[TFM-4AS-1]].<ref name="pmid23231475">{{cite journal | vauthors = Zhang X, Sui Z | title = Deciphering the selective androgen receptor modulators paradigm | journal = Expert Opin Drug Discov | volume = 8 | issue = 2 | pages = 191–218 | date = February 2013 | pmid = 23231475 | doi = 10.1517/17460441.2013.741582 | url = }}</ref>


MK-0773 is a [[4-azasteroid]]<ref name="LagojdaKuehne2016">{{cite journal|last1=Lagojda|first1=Andreas|last2=Kuehne|first2=Dirk|last3=Krug|first3=Oliver|last4=Thomas|first4=Andreas|last5=Wigger|first5=Tina|last6=Karst|first6=Uwe|last7=Schänzer|first7=Wilhelm|last8=Thevis|first8=Mario|title=Identification of selected in vitro generated phase-I metabolites of the steroidal selective androgen receptor modulator MK-0773 for doping control purposes|journal=European Journal of Mass Spectrometry|volume=22|issue=2|year=2016|pages=49|issn=1356-1049|doi=10.1255/ejms.1415}}</ref> and a [[potency (pharmacology)|potent]] and [[binding selectivity|selective]] [[agonist]] of the [[androgen receptor]] (AR).<ref name="pmid20356837" /> It binds to the AR with an [[IC50|IC<sub>50</sub>]] of 6.6&nbsp;nM and is a [[partial agonist]] in transactivation modulation of the AR with an IP of 25&nbsp;nM and E<sub>max</sub> of 78% and has a [[Nuclear receptor coactivator 2|TRAF2]] E<sub>max </sub>of 29% and a [[virilization]] (N/C interaction) counterscreen assay E<sub>max</sub> of 2%.<ref name="pmid20356837" /> That is, it produces promoter activation but induces the N/C interaction almost negligibly.<ref name="pmid20356837" /> MK-0773 is reportedly four times as potent as [[testosterone (medication)|testosterone]] as an [[agonist]] of the [[androgen receptor]].<ref name="Ph.D.2013" /> The drug is selective and does not bind to other [[steroid hormone receptor]]s such as the [[progesterone receptor]] or [[glucocorticoid receptor]] and shows no significant [[enzyme inhibitor|inhibition]] of [[5α-reductase]] (IC<sub>50</sub> > 10&nbsp;μM).<ref name="pmid20356837" /> In addition, it is non-[[aromatase|aromatizable]] and hence has no potential for [[estrogen]]ic effects or [[side effect]]s, like [[gynecomastia]].<ref name="StochFriedman2010">{{cite journal|last1=Stoch|first1=SA|last2=Friedman|first2=EJ|last3=Zhou|first3=Y|last4=Zhu|first4=H|last5=Larson|first5=P|last6=Binkowitz|first6=B|last7=Chodakewitz|first7=J|last8=Wagner|first8=JA|title=Biomarkers of Bone Metabolism and Serum Free Estradiol (E2) Levels in Medically Castrated Older Men Treated with MK-0773 (MK), Testosterone (T), or Placebo (PBO) for 12 Weeks.|year=2010|pages=OR08-5–OR08-5|doi=10.1210/endo-meetings.2010.PART1.OR.OR08-5}}</ref> MK-0773 had similar effects on [[lipid]] [[metabolism]] relative to DHT, including a decrease in total [[cholesterol]] and [[high-density lipoprotein]] (HDL) of a similar magnitude.<ref name="pmid20356837" />
MK-0773 is a [[4-azasteroid]]<ref name="LagojdaKuehne2016">{{cite journal | vauthors = Lagojda A, Kuehne D, Krug O, Thomas A, Wigger T, Karst U, Schänzer W, Thevis M | display-authors = 6 | title = Identification of selected in vitro generated phase-I metabolites of the steroidal selective androgen receptor modulator MK-0773 for doping control purposes | journal = European Journal of Mass Spectrometry | volume = 22 | issue = 2 | pages = 49–59 | year = 2016 | pmid = 27419898 | doi = 10.1255/ejms.1415 | s2cid = 207191784 }}</ref> and a [[potency (pharmacology)|potent]] and [[binding selectivity|selective]] [[agonist]] of the [[androgen receptor]] (AR).<ref name="pmid20356837" /> It binds to the AR with an [[EC50|EC<sub>50</sub>]] of 6.6&nbsp;nM and is a [[partial agonist]] in [[transactivation]] modulation of the AR with an IP of 25&nbsp;nM and E<sub>max</sub> of 78% and has a [[Nuclear receptor coactivator 2|TRAF2]] E<sub>max </sub>of 29% and an N/C interaction (virilization-related) counterscreen assay E<sub>max</sub> of 2%.<ref name="pmid20356837" /> That is, it produces promoter activation but induces the N/C interaction almost negligibly.<ref name="pmid20356837" /> MK-0773 is reportedly four times as potent as [[testosterone (medication)|testosterone]] as an agonist of the AR.<ref name="Ph.D.2013" /> The drug is selective and does not bind to other [[steroid hormone receptor]]s such as the [[progesterone receptor]] or [[glucocorticoid receptor]] and shows no significant [[enzyme inhibitor|inhibition]] of [[5α-reductase]] (IC<sub>50</sub> > 10&nbsp;μM).<ref name="pmid20356837" /> In addition, it is non-[[aromatase|aromatizable]] and hence has no potential for [[estrogen]]ic effects or [[side effect]]s, like [[gynecomastia]].<ref name="StochFriedman2010">{{cite journal| vauthors = Stoch SA, Friedman EJ, Zhou Y, Zhu H, Larson P, Binkowitz B, Chodakewitz J, Wagner JA | display-authors = 6 |title=Biomarkers of Bone Metabolism and Serum Free Estradiol (E2) Levels in Medically Castrated Older Men Treated with MK-0773 (MK), Testosterone (T), or Placebo (PBO) for 12 Weeks. | journal = Endocrine Reviews | date = June 2010 | volume = 31 | issue = 3 | pages = S48 }}</ref> MK-0773 had similar effects on [[lipid]] [[metabolism]] relative to DHT, including a decrease in total [[cholesterol]] and [[high-density lipoprotein]] (HDL) of a similar magnitude.<ref name="pmid20356837" />


MK-0773 shows tissue-selective androgenic effects ''[[in vivo]]'' in animals.<ref name="pmid20356837" /> It increases [[lean body mass]] with maximal [[anabolic]] effects that are approximately 80% of those of [[dihydrotestosterone]] (DHT).<ref name="pmid20356837" /> However, it had less than 5% of the effect of DHT on [[uterus|uterine weight]], about 30 to 50% of the increase of [[sebaceous gland]] area induced by DHT, and increased the weight of the [[seminal vesicle]]s by 12% of that of DHT at the highest dosage assessed.<ref name="pmid20356837" /> It had similarly reduced effects on the [[prostate gland]].<ref name="pmid20356837" /> No significant increase in [[gene expression]] of six candidate [[gene]]s of virilization was observed.<ref name="LittmanKrishna2011" /> As such, MK-0773 shows a profile of an anabolic SARM with limited effects on sebaceous glands and [[reproductive system|reproductive tissue]]s in animals and a minimal propensity for virilization.<ref name="pmid20356837" />
MK-0773 shows tissue-selective androgenic effects ''[[in vivo]]'' in animals.<ref name="pmid20356837" /> It increases [[lean body mass]] with maximal [[anabolic]] effects that are approximately 80% of those of [[dihydrotestosterone]] (DHT).<ref name="pmid20356837" /> However, it had less than 5% of the effect of DHT on [[uterus|uterine weight]], about 30 to 50% of the increase of [[sebaceous gland]] area induced by DHT, and increased the weight of the [[seminal vesicle]]s by 12% of that of DHT at the highest dosage assessed.<ref name="pmid23231475" /><ref name="pmid20356837" /> It had similarly reduced effects on the [[prostate gland]].<ref name="pmid20356837" /> No significant increase in [[gene expression]] of six candidate [[gene]]s related to [[virilization]] was observed.<ref name="LittmanKrishna2011" /> As such, MK-0773 shows a profile of an anabolic SARM with limited effects on sebaceous glands and [[reproductive system|reproductive tissue]]s in animals and a reduced propensity for virilization.<ref name="pmid20356837" />


In human clinical studies, MK-0773 produced anabolism in women and men while producing no or very low effects on sebaceous glands, the [[endometrium]], or the prostate gland after 12 weeks of treatment.<ref name="pmid20356837" /><ref name="LittmanKrishna2011">{{cite book|author1=Bruce H. Littman|author2=Rajesh Krishna|title=Translational Medicine and Drug Discovery|url=https://books.google.com/books?id=cJif7ofwbcEC&pg=PA136|date=31 January 2011|publisher=Cambridge University Press|isbn=978-1-139-49872-2|pages=136–}}</ref> The decrease in total cholesterol and HDL was also observed in the clinical studies.<ref name="pmid20356837" /> MK-0773 produced a significant increase in lean body mass in elderly (≥65 years of age) women with sarcopenia and moderate physical dysfunction.<ref name="PapanicolaouAther2013">{{cite journal|last1=Papanicolaou|first1=Dimitris A.|last2=Ather|first2=S. N.|last3=Zhu|first3=H.|last4=Zhou|first4=Y.|last5=Lutkiewicz|first5=J.|last6=Scott|first6=B. B.|last7=Chandler|first7=J.|title=A phase IIA randomized, placebo-controlled clinical trial to study the efficacy and safety of the selective androgen receptor modulator (SARM), MK-0773 in female participants with sarcopenia|journal=The journal of nutrition, health & aging|volume=17|issue=6|year=2013|pages=533–543|issn=1279-7707|doi=10.1007/s12603-013-0335-x}}</ref><ref name="Cox2016">{{cite book|author=Chad Cox|title=Clinical Nutrition and Aging: Sarcopenia and Muscle Metabolism|url=https://books.google.com/books?id=U3amCwAAQBAJ&pg=PA258|date=24 February 2016|publisher=Apple Academic Press|isbn=978-1-77188-371-9|pages=258–}}</ref><ref name="HollandBreitbart2015">{{cite book|author1=Jimmie C. Holland|author2=William S. Breitbart|author3=Paul B. Jacobsen|coauthors=Phyllis N. Butow, Matthew J. Loscalzo, Ruth McCorkle|title=Psycho-Oncology|url=https://books.google.com/books?id=oy9mBgAAQBAJ&pg=PA242|date=23 April 2015|publisher=Oxford University Press|isbn=978-0-19-936331-5|pages=242–}}</ref> It also increased muscle strength relative to [[placebo]] but this failed to reach [[statistical significance]].<ref name="PapanicolaouAther2013" /><ref name="HollandBreitbart2015" /> MK-0773 has been associated with [[elevated transaminases|elevated liver enzymes]] in clinical studies.<ref name="PapanicolaouAther2013" />
In human clinical studies, MK-0773 produced anabolism in women and men while producing no or very low effects on sebaceous glands, the [[endometrium]], or the prostate gland after 12 weeks of treatment.<ref name="pmid20356837" /><ref name="LittmanKrishna2011">{{cite book | vauthors = Stoch SA | chapter = Bone Disorders: Translational Medicine Case Studies | veditors = Littman BH, Krishna R |title=Translational Medicine and Drug Discovery|chapter-url=https://books.google.com/books?id=cJif7ofwbcEC&pg=PA136|date=31 January 2011|publisher=Cambridge University Press|isbn=978-1-139-49872-2|pages=136– | doi = 10.1017/CBO9780511976087.007 }}</ref><ref name="StochFriedmanZhu2008">Stoch SA, Friedman EJ, Zhu H, Xu Y, Wong P, Chappell DL, et al. (2008). A 12-week pharmacokinetic and pharmacodynamic (PD) study of MK-0773 in healthy postmenopausal (PMP) subjects. The Endocrine Society 90th Annual Meeting, June 12–15, San Francisco, CA. Abst. OR35–33.</ref><ref name="Stoch2009">Stoch SA, et al. (2009) 91st Annual Meeting of the Endocrine Society, Washington, D.C. Abst. S21–24.</ref> A decrease in total cholesterol and HDL was also observed in the clinical studies.<ref name="pmid20356837" /> MK-0773 produced a significant increase in lean body mass in elderly (≥65 years of age) women with sarcopenia and moderate physical dysfunction.<ref name="PapanicolaouAther2013">{{cite journal | vauthors = Papanicolaou DA, Ather SN, Zhu H, Zhou Y, Lutkiewicz J, Scott BB, Chandler J | title = A phase IIA randomized, placebo-controlled clinical trial to study the efficacy and safety of the selective androgen receptor modulator (SARM), MK-0773 in female participants with sarcopenia | journal = The Journal of Nutrition, Health & Aging | volume = 17 | issue = 6 | pages = 533–543 | year = 2013 | pmid = 23732550 | doi = 10.1007/s12603-013-0335-x | s2cid = 42439768 | doi-access = free }}</ref><ref name="pmid25566189">{{cite journal | vauthors = Basualto-Alarcón C, Varela D, Duran J, Maass R, Estrada M | title = Sarcopenia and Androgens: A Link between Pathology and Treatment | journal = Frontiers in Endocrinology | volume = 5 | issue = | pages = 217 | date = 2014 | pmid = 25566189 | pmc = 4270249 | doi = 10.3389/fendo.2014.00217 | isbn = 9781771883719 | url = https://books.google.com/books?id=U3amCwAAQBAJ&pg=PA258 | doi-access = free }}</ref><ref name="HollandBreitbart2015">{{cite book| vauthors = MacDonald N | chapter = Weight and Appetite Loss in Cancer | veditors = Holland JC, Breitbart WS, Jacobsen PB, Butow PN, Loscalzo MJ, McCorkle R |title=Psycho-Oncology | chapter-url = https://books.google.com/books?id=oy9mBgAAQBAJ&pg=PA242|date=23 April 2015|publisher=Oxford University Press|isbn=978-0-19-936331-5|pages=242–}}</ref> It also increased muscle strength relative to [[placebo]] but this failed to reach [[statistical significance]].<ref name="PapanicolaouAther2013" /><ref name="HollandBreitbart2015" /> MK-0773 has been associated with [[elevated transaminases|elevated liver enzymes]] in clinical studies.<ref name="PapanicolaouAther2013" />


==See also==
== See also ==
* [[TFM-4AS-1]]
* [[YK-11]]
* [[YK-11]]


==References==
== References ==
{{Reflist|2}}
{{Reflist}}



{{Androgen receptor modulators}}
{{Androgen receptor modulators}}


⚫
[[Category:Abandoned drugs]]
[[Category:Androstanes]]
[[Category:Androstanes]]
[[Category:Carboxamides]]
[[Category:Carboxamides]]
[[Category:Imidazopyridines]]
[[Category:Imidazopyridines]]
⚫
[[Category:Ketones]]
[[Category:Organofluorides]]
[[Category:Organofluorides]]
[[Category:Selective androgen receptor modulators]]
[[Category:Selective androgen receptor modulators]]

Latest revision as of 03:24, 5 February 2024

MK-0773
Clinical data
Other namesPF-05314882; N-(3H-Imidazo(4,5-b)pyridin-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide
Routes of
administration		By mouth
Identifiers
  • (1S,3aS,3bS,5aR,9aS,9bS,11aS)-8-Fluoro-N-(1H-imidazo[4,5-b]pyridin-2-ylmethyl)-6,9a,11a-trimethyl-7-oxo-2,3,3a,3b,4,5,5a,9b,10,11-decahydro-1H-indeno[5,4-f]quinoline-1-carboxamide
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC27H34FN5O2
Molar mass479.600 g·mol−1
3D model (JSmol)
  • C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@@H]2C(=O)NCC4=NC5=C(N4)C=CC=N5)CC[C@@H]6[C@@]3(C=C(C(=O)N6C)F)C
  • InChI=1S/C27H34FN5O2/c1-26-11-10-17-15(6-9-21-27(17,2)13-19(28)25(35)33(21)3)16(26)7-8-18(26)24(34)30-14-22-31-20-5-4-12-29-23(20)32-22/h4-5,12-13,15-18,21H,6-11,14H2,1-3H3,(H,30,34)(H,29,31,32)/t15-,16-,17-,18+,21+,26-,27+/m0/s1
  • Key:GBEUKTWTUSPHEE-JWJWXJQQSA-N

MK-0773, also known as PF-05314882, is a steroidal, orally active selective androgen receptor modulator (SARM) that was under development by Merck and GTx for the treatment of sarcopenia (loss of muscle mass) in women and men.[1][2][3] Clinical trials for sarcopenia began in late 2007 but the collaboration between Merck and GTx ended in early 2010 and GTx terminated development of MK-0773 shortly thereafter.[2] MK-0773 was developed as a more advanced version of the related compound TFM-4AS-1.[4]

MK-0773 is a 4-azasteroid[5] and a potent and selective agonist of the androgen receptor (AR).[1] It binds to the AR with an EC50 of 6.6 nM and is a partial agonist in transactivation modulation of the AR with an IP of 25 nM and Emax of 78% and has a TRAF2 Emax of 29% and an N/C interaction (virilization-related) counterscreen assay Emax of 2%.[1] That is, it produces promoter activation but induces the N/C interaction almost negligibly.[1] MK-0773 is reportedly four times as potent as testosterone as an agonist of the AR.[2] The drug is selective and does not bind to other steroid hormone receptors such as the progesterone receptor or glucocorticoid receptor and shows no significant inhibition of 5α-reductase (IC50 > 10 μM).[1] In addition, it is non-aromatizable and hence has no potential for estrogenic effects or side effects, like gynecomastia.[6] MK-0773 had similar effects on lipid metabolism relative to DHT, including a decrease in total cholesterol and high-density lipoprotein (HDL) of a similar magnitude.[1]

MK-0773 shows tissue-selective androgenic effects in vivo in animals.[1] It increases lean body mass with maximal anabolic effects that are approximately 80% of those of dihydrotestosterone (DHT).[1] However, it had less than 5% of the effect of DHT on uterine weight, about 30 to 50% of the increase of sebaceous gland area induced by DHT, and increased the weight of the seminal vesicles by 12% of that of DHT at the highest dosage assessed.[4][1] It had similarly reduced effects on the prostate gland.[1] No significant increase in gene expression of six candidate genes related to virilization was observed.[7] As such, MK-0773 shows a profile of an anabolic SARM with limited effects on sebaceous glands and reproductive tissues in animals and a reduced propensity for virilization.[1]

In human clinical studies, MK-0773 produced anabolism in women and men while producing no or very low effects on sebaceous glands, the endometrium, or the prostate gland after 12 weeks of treatment.[1][7][8][9] A decrease in total cholesterol and HDL was also observed in the clinical studies.[1] MK-0773 produced a significant increase in lean body mass in elderly (≥65 years of age) women with sarcopenia and moderate physical dysfunction.[10][11][12] It also increased muscle strength relative to placebo but this failed to reach statistical significance.[10][12] MK-0773 has been associated with elevated liver enzymes in clinical studies.[10]

See also

[edit]

References

[edit]
  1. ^ a b c d e f g h i j k l m Schmidt A, Kimmel DB, Bai C, Scafonas A, Rutledge S, Vogel RL, et al. (May 2010). "Discovery of the selective androgen receptor modulator MK-0773 using a rational development strategy based on differential transcriptional requirements for androgenic anabolism versus reproductive physiology". The Journal of Biological Chemistry. 285 (22): 17054–17064. doi:10.1074/jbc.M109.099002. PMC 2878020. PMID 20356837.
  2. ^ a b c Newton DE (26 November 2013). "Problems, Controversies, and Solutions". Steroids and Doping in Sports: A Reference Handbook: A Reference Handbook. ABC-CLIO. pp. 85–. ISBN 978-1-61069-314-1.
  3. ^ "MK 0773". AdisInsight. Springer Nature Switzerland AG.
  4. ^ a b Zhang X, Sui Z (February 2013). "Deciphering the selective androgen receptor modulators paradigm". Expert Opin Drug Discov. 8 (2): 191–218. doi:10.1517/17460441.2013.741582. PMID 23231475.
  5. ^ Lagojda A, Kuehne D, Krug O, Thomas A, Wigger T, Karst U, et al. (2016). "Identification of selected in vitro generated phase-I metabolites of the steroidal selective androgen receptor modulator MK-0773 for doping control purposes". European Journal of Mass Spectrometry. 22 (2): 49–59. doi:10.1255/ejms.1415. PMID 27419898. S2CID 207191784.
  6. ^ Stoch SA, Friedman EJ, Zhou Y, Zhu H, Larson P, Binkowitz B, et al. (June 2010). "Biomarkers of Bone Metabolism and Serum Free Estradiol (E2) Levels in Medically Castrated Older Men Treated with MK-0773 (MK), Testosterone (T), or Placebo (PBO) for 12 Weeks". Endocrine Reviews. 31 (3): S48.
  7. ^ a b Stoch SA (31 January 2011). "Bone Disorders: Translational Medicine Case Studies". In Littman BH, Krishna R (eds.). Translational Medicine and Drug Discovery. Cambridge University Press. pp. 136–. doi:10.1017/CBO9780511976087.007. ISBN 978-1-139-49872-2.
  8. ^ Stoch SA, Friedman EJ, Zhu H, Xu Y, Wong P, Chappell DL, et al. (2008). A 12-week pharmacokinetic and pharmacodynamic (PD) study of MK-0773 in healthy postmenopausal (PMP) subjects. The Endocrine Society 90th Annual Meeting, June 12–15, San Francisco, CA. Abst. OR35–33.
  9. ^ Stoch SA, et al. (2009) 91st Annual Meeting of the Endocrine Society, Washington, D.C. Abst. S21–24.
  10. ^ a b c Papanicolaou DA, Ather SN, Zhu H, Zhou Y, Lutkiewicz J, Scott BB, Chandler J (2013). "A phase IIA randomized, placebo-controlled clinical trial to study the efficacy and safety of the selective androgen receptor modulator (SARM), MK-0773 in female participants with sarcopenia". The Journal of Nutrition, Health & Aging. 17 (6): 533–543. doi:10.1007/s12603-013-0335-x. PMID 23732550. S2CID 42439768.
  11. ^ Basualto-Alarcón C, Varela D, Duran J, Maass R, Estrada M (2014). "Sarcopenia and Androgens: A Link between Pathology and Treatment". Frontiers in Endocrinology. 5: 217. doi:10.3389/fendo.2014.00217. ISBN 9781771883719. PMC 4270249. PMID 25566189.
  12. ^ a b MacDonald N (23 April 2015). "Weight and Appetite Loss in Cancer". In Holland JC, Breitbart WS, Jacobsen PB, Butow PN, Loscalzo MJ, McCorkle R (eds.). Psycho-Oncology. Oxford University Press. pp. 242–. ISBN 978-0-19-936331-5.
Retrieved from "https://en.wikipedia.org/w/index.php?title=MK-0773&oldid=1203548178"