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Figure 5
Primate body weight from day −21, through 28 days dosing and 21 days postdosing with*RAD140*(0.01, 0.1, and 1 mg/kg, po).25*Three monkeys were included for each treatment group. The change in baseline subtracted body weight from day −1*...
Due to the small group size (n*= 3 for each dosing group), we used each animal’s background weight change for the weeks prior to the experiment to establish the baseline as control. Since the mean body weight for each group of three monkeys converged to an almost identical number (day −1), with the absolute body weight range between groups of only 4.26−4.29 kg, we plotted the absolute body weight in Figure*Figure5.5. In this study, a mean weight gain of greater than 10% in just 28 days of dosing was achieved at a dose of just 0.1 mg/kg, with a similar effect observed at the 1.0 mg/kg dosing group.26
Dual energy X-ray absorptiometry (“DEXA”) scans of all monkeys were taken two days before dosing began and one day after the final dose (day −2 and day 29) in order to determine the effects of*RAD140*on lean tissue and fat; the results are shown in Figure*Figure6.6. As can be seen, there was no consistent effect on absolute fat mass, whereas muscle showed a qualitative trend that increases with dose. Although it appears that the majority of mass increase shown in Figure*Figure55*was due to lean mass increase, none of the tissue weight increases were quite statistically significant (p*> 0.05), which might be due to the small group sizes (n*= 3) and relatively large standard deviations.27
[https://www]
Figure 6
Mean change in primate tissue weight as measured by DEXA analysis at day −2 and day 29. Standard deviation for fat (36, 36, 40) and lean tissue (65, 205, 188) for 0.01 mg/kg, 0.1 mg/kg, and 1.0 mg/kg, respectively. None of the changes were statistically*...
Clinical chemistry indicated the expected lowering of lipids (LDL, HDL, triglycerides).28*Despite the rather dramatic increases in body weight over such a short time, there was no elevation of liver enzyme transaminase levels in any animal at any dose >2 fold over its baseline value.29,30*Given the well-established relationship between oral androgen use and liver stress indicators, we were quite pleased that at a dose 10-fold greater than the fully effective dose we saw minimal liver enzyme elevations.31Taken in sum,*RAD140*has all the hallmarks of a SARM. It is potency selective, since it stimulates muscle weight increases at a lower dose than that required to stimulate prostate weight increases. Moreover, it is also efficacy selective, because it is fully anabolic on muscle but demonstrates less than complete efficacy on the prostate and seminal vesicles and, in fact, can partially antagonize the stimulation of the seminal vesicles induced by testosterone.*RAD140*has excellent pharmacokinetics and is a potent anabolic in nonhuman primates as well. We believe the overall preclinical profile of*RAD140*is very good, and the compound has completed preclinical toxicology in both rats and monkeys. We are currently preparing*RAD140*for phase I clinical studies in patients suffering from severe weight loss due to cancer cachexia.
Supporting Information Available
Synthetic methods, NMR spectra, and biological assays. This material is available free of charge via the Internet at*http://pubs.acs.org.
Supplementary Material
ml1002508_si_001.pdf(379K, pdf)
Article information
ACS Med Chem Lett. 2011 Feb 10; 2(2): 124–129.
Published online 2010 Dec 2.*doi:*10.1021/ml1002508
PMCID:*PMC4018048
PMID:*24900290
Chris P. Miller,[https://www]*†*Maysoun Shomali,†*C. Richard Lyttle,†*Louis St. L. O’Dea,†*Hillary Herendeen,†*Kyla Gallacher,†*Dottie Paquin,†*Dennis R. Compton,‡*Bishwabhusan Sahoo,‡*Sean A. Kerrigan,‡*Matthew S. Burge,‡*Michael Nickels,‡*Jennifer L. Green,‡*John A. Katzenellenbogen,§*Alexei Tchesnokov,∥*and*Gary Hattersley†
†Radius Health, Inc., 300 Technology Square, Cambridge, Massachusetts 02139, United States
‡Obiter Research, 2809 Gemini Court, Champaign, Illinois 61822-9647, United States
§Department of Chemistry, University of Illinois at Urbana−Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, United States
∥Cambridge Major Laboratories, Inc., W130 N10497 Washington Drive, Germantown, Wisconsin 53022, United States
[https://www]Corresponding author.
*E-mail:*moc.mrahpsuidar@rellimc.
Received 2010 Aug 17; Accepted 2010 Nov 15.
Copyright*
2010 American Chemical Society
This article has been*cited by*other articles in PMC.
Articles from*ACS Medicinal Chemistry Letters*are provided here courtesy of*American Chemical Society
References
Lu N. Z.; Wardell S. E.; Burnstein K. L.; Defranco D.; Fuller P. J.; Giguere V.; Hochberg R. B.; McKay L.; Renoir J. M.; Weigel N. L.; Wilson E. M.; McDonnell D. P.; Cidlowski J. A.*International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors.*Pharmacol. Rev.*2007,*584782–97. [PubMed]*[Google Scholar]
Testosterone Action Deficiency Substitution, 3rd ed.; Nieschlag E., Behre H., Eds.; Cambridge University Press: 2004.*[Google Scholar]
Kilbourne E. J.; Moore W. J.; Freedman L. P.; Nagpal S.*Selective androgen receptor modulators for frailty and osteoporosis.*Curr. Opin. Invest. Drugs*2007,*810821–829. [PubMed]*[Google Scholar]
Bhasin S.; Jasuja R.*Selective androgen receptor modulators as function promoting therapies.*Curr. Opin. Clin. Nutrition Metab. Care*2009,*123232–240.*[PMC free article]*[PubMed]*[Google Scholar]
Mohler M. L.; Bohl C. E.; Narayanan R.; He Y.; Hwang D. J.; Dalton J. T.; Miller D. D.*Nonsteroidal tissue-selective androgen receptor modulators.*Methods Principles Med. Chem.*2008,*39, 249–304 (Nuclear Receptors as Drug Targets).*[Google Scholar]
Kim J.; Wu D.; Hwang D. J.; Miller D. D.; Dalton J. T.*The para substituent of*S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamides is a major structural determinant of in vivo disposition and activity of selective androgen receptor modulators.*J. Pharmacol. Experimental Therapeutics*2005,*3151230–239. [PubMed]*[Google Scholar]
Ostrowski J.; Kuhns J. E.; L J. A.; M M. C.; Beehler B. C.; Krystek S. R. Jr.; B Y.; Sun C.; Seethala R.; Golla R.; Sleph P. G.; Fura A.; An Y.; Kish K. F.; Sack J. S.; Mookhtiar K. A.; Grover G. J.; Hamann L. G.*Pharmacological and X-ray structural characterization of a novel selective androgen receptor modulator: potent hyperanabolic stimulation of skeletal muscle with hypostimulation of prostate in rats.*Endocrinology*2007,*14814–12. [PubMed]*[Google Scholar]
Gao W.; Bohl C. E.; Dalton J. T.*Chemistry and structural biology of the androgen receptor.*Chem. Rev.*2005,*10593352–3370.*[PMC free article]*[PubMed]*[Google Scholar]
Gao W.; Dalton J. T.*Ockham’s razor and selective androgen receptors (SARMs): Are we overlooking the role of 5α-reductase?.*Mol. Interventions*2007,*7110–13.*[PMC free article]*[PubMed]*[Google Scholar]
pK*data in rats for compound*3*is provided in the*Supporting Information.
Oral data for compounds*3*and*4*in the Herschberger assay is shown in the*Supporting Information.
Human and rat microsome data are shown in the*Supporting Information.
The left-hand side of the molecule as written is presumed to overlay with the A-ring of testosterone. This particular left-hand side equivalent has been utilized to good effect previously in nonsteroidal SARMs:
a.*Li J. J.; Sutton J. C.; Nirschl A.; Zou Y.; Wang H.; Sun C.; Pi Z.; Johnson R.; Krystek S. R. Jr.; Seethala R.; Golla R.; Sleph P. G.; Beehler B. C.; Grover G. J.; Fura A.; Vyas V. P.; Li C. Y.; Gougoutas J. Z.; Galella M. A.; Michael A.; Zahler R.; Ostrowski J.; Hamann L. G.*Discovery of Potent and Muscle Selective Androgen Receptor Modulators through Scaffold Modifications.*J. Med. Chem.*2007,*50133015–3025. The precursor fragment*6*has been described for the preparation of SARMs in: . [PubMed]*[Google Scholar]
b.*Schlienger N.; Lund B. W.; Pawlas J.; Badalassi F.; Bertozzi F.; Lewinsky R.; Fejzic A.; Thygesen M. B.; Tabatabaei A.; Bradley S. R.; Gardell L. R.; Piu F.; Olsson R.*Synthesis, structure−activity relationships, and characterization of novel nonsteroidal and selective androgen receptor modulators.*J. Med. Chem.*2009,*52, 7186–7191. [PubMed]*[Google Scholar]
US2010/0041721.
Wipf P.; Miller C. P.*A new synthesis of highly functionalized oxazoles.*J. Org. Chem.*1993,*58143604–3606.*[Google Scholar]
Johns B. A.; Weatherhead J. G.; Allen S. H.; Thompson J. B.; Garvey E. P.; Foster S. A.; Jeffrey J. L.; Miller W. H.*1,3,4-Oxadiazole substituted naphthyridines as HIV-1 integrase inhibitors. Part 2: SAR of the C5 position.*Biorg. Med. Chem. Lett.*2009,*1961807–1810. [PubMed]*[Google Scholar]
The scheme shown was used to successfully produce approximately 2 kg of compound*5*in >99% purity under GMP manufacturing conditions.
The AR binding assay was performed as specified from the manufacturer. The assay is a fluorometric assay using a tracer made from fluorescent tagged AR-ligand methyltrienolone (R1881).*Ki*values were derived by the Cheng−Prushoff equation (Ki*= (IC50/(1 + /Km)), where*Km*was set equal to*Kd,*Kd*= 25 nM (fluorometric R1881), and = 1.
The C2C12 osteoblast differentiation assay procedure is explained in the*Supporting Information.
Hershberger L. G.; Shipley E. G.; Meyer R. K.*Myotropic activity of 19-nortestosterone and other steroids determined by a modified levator ani muscle method.*Proc. Soc. Exp. Biol. Med.*1953,*83, 175–80. [PubMed]*[Google Scholar]
This dose of TP provides an approximate EC70*on prostate and EC90*on muscle in our Herschberger assays.
RAD140*demonstrated*fairly*linear increases in exposure in male rats up through the 10 mg/kg po dose range, thereby ruling out an exposure limited efficacy as opposed to compound-limited efficacy. Antagonism of TP is further evidence of a mechanism-specific, limited efficacy as opposed to a pharmacokinetic limitation of the compound.
Testosterone levels in castrated rats are
UNCLE Z REP
WWW.UNCLEZ.RU FOR LIST/ORDERING
PM OR EMAIL FOR QUESTIONS/INQUIRIES BUMPMAN82@PROTONMAIL.COM
[https://www]
Figure 5
Primate body weight from day −21, through 28 days dosing and 21 days postdosing with*RAD140*(0.01, 0.1, and 1 mg/kg, po).25*Three monkeys were included for each treatment group. The change in baseline subtracted body weight from day −1*...
Due to the small group size (n*= 3 for each dosing group), we used each animal’s background weight change for the weeks prior to the experiment to establish the baseline as control. Since the mean body weight for each group of three monkeys converged to an almost identical number (day −1), with the absolute body weight range between groups of only 4.26−4.29 kg, we plotted the absolute body weight in Figure*Figure5.5. In this study, a mean weight gain of greater than 10% in just 28 days of dosing was achieved at a dose of just 0.1 mg/kg, with a similar effect observed at the 1.0 mg/kg dosing group.26
Dual energy X-ray absorptiometry (“DEXA”) scans of all monkeys were taken two days before dosing began and one day after the final dose (day −2 and day 29) in order to determine the effects of*RAD140*on lean tissue and fat; the results are shown in Figure*Figure6.6. As can be seen, there was no consistent effect on absolute fat mass, whereas muscle showed a qualitative trend that increases with dose. Although it appears that the majority of mass increase shown in Figure*Figure55*was due to lean mass increase, none of the tissue weight increases were quite statistically significant (p*> 0.05), which might be due to the small group sizes (n*= 3) and relatively large standard deviations.27
[https://www]
Figure 6
Mean change in primate tissue weight as measured by DEXA analysis at day −2 and day 29. Standard deviation for fat (36, 36, 40) and lean tissue (65, 205, 188) for 0.01 mg/kg, 0.1 mg/kg, and 1.0 mg/kg, respectively. None of the changes were statistically*...
Clinical chemistry indicated the expected lowering of lipids (LDL, HDL, triglycerides).28*Despite the rather dramatic increases in body weight over such a short time, there was no elevation of liver enzyme transaminase levels in any animal at any dose >2 fold over its baseline value.29,30*Given the well-established relationship between oral androgen use and liver stress indicators, we were quite pleased that at a dose 10-fold greater than the fully effective dose we saw minimal liver enzyme elevations.31Taken in sum,*RAD140*has all the hallmarks of a SARM. It is potency selective, since it stimulates muscle weight increases at a lower dose than that required to stimulate prostate weight increases. Moreover, it is also efficacy selective, because it is fully anabolic on muscle but demonstrates less than complete efficacy on the prostate and seminal vesicles and, in fact, can partially antagonize the stimulation of the seminal vesicles induced by testosterone.*RAD140*has excellent pharmacokinetics and is a potent anabolic in nonhuman primates as well. We believe the overall preclinical profile of*RAD140*is very good, and the compound has completed preclinical toxicology in both rats and monkeys. We are currently preparing*RAD140*for phase I clinical studies in patients suffering from severe weight loss due to cancer cachexia.
Supporting Information Available
Synthetic methods, NMR spectra, and biological assays. This material is available free of charge via the Internet at*http://pubs.acs.org.
Supplementary Material
ml1002508_si_001.pdf(379K, pdf)
Article information
ACS Med Chem Lett. 2011 Feb 10; 2(2): 124–129.
Published online 2010 Dec 2.*doi:*10.1021/ml1002508
PMCID:*PMC4018048
PMID:*24900290
Chris P. Miller,[https://www]*†*Maysoun Shomali,†*C. Richard Lyttle,†*Louis St. L. O’Dea,†*Hillary Herendeen,†*Kyla Gallacher,†*Dottie Paquin,†*Dennis R. Compton,‡*Bishwabhusan Sahoo,‡*Sean A. Kerrigan,‡*Matthew S. Burge,‡*Michael Nickels,‡*Jennifer L. Green,‡*John A. Katzenellenbogen,§*Alexei Tchesnokov,∥*and*Gary Hattersley†
†Radius Health, Inc., 300 Technology Square, Cambridge, Massachusetts 02139, United States
‡Obiter Research, 2809 Gemini Court, Champaign, Illinois 61822-9647, United States
§Department of Chemistry, University of Illinois at Urbana−Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, United States
∥Cambridge Major Laboratories, Inc., W130 N10497 Washington Drive, Germantown, Wisconsin 53022, United States
[https://www]Corresponding author.
*E-mail:*moc.mrahpsuidar@rellimc.
Received 2010 Aug 17; Accepted 2010 Nov 15.
Copyright*
2010 American Chemical SocietyThis article has been*cited by*other articles in PMC.
Articles from*ACS Medicinal Chemistry Letters*are provided here courtesy of*American Chemical Society
References
Lu N. Z.; Wardell S. E.; Burnstein K. L.; Defranco D.; Fuller P. J.; Giguere V.; Hochberg R. B.; McKay L.; Renoir J. M.; Weigel N. L.; Wilson E. M.; McDonnell D. P.; Cidlowski J. A.*International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors.*Pharmacol. Rev.*2007,*584782–97. [PubMed]*[Google Scholar]
Testosterone Action Deficiency Substitution, 3rd ed.; Nieschlag E., Behre H., Eds.; Cambridge University Press: 2004.*[Google Scholar]
Kilbourne E. J.; Moore W. J.; Freedman L. P.; Nagpal S.*Selective androgen receptor modulators for frailty and osteoporosis.*Curr. Opin. Invest. Drugs*2007,*810821–829. [PubMed]*[Google Scholar]
Bhasin S.; Jasuja R.*Selective androgen receptor modulators as function promoting therapies.*Curr. Opin. Clin. Nutrition Metab. Care*2009,*123232–240.*[PMC free article]*[PubMed]*[Google Scholar]
Mohler M. L.; Bohl C. E.; Narayanan R.; He Y.; Hwang D. J.; Dalton J. T.; Miller D. D.*Nonsteroidal tissue-selective androgen receptor modulators.*Methods Principles Med. Chem.*2008,*39, 249–304 (Nuclear Receptors as Drug Targets).*[Google Scholar]
Kim J.; Wu D.; Hwang D. J.; Miller D. D.; Dalton J. T.*The para substituent of*S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamides is a major structural determinant of in vivo disposition and activity of selective androgen receptor modulators.*J. Pharmacol. Experimental Therapeutics*2005,*3151230–239. [PubMed]*[Google Scholar]
Ostrowski J.; Kuhns J. E.; L J. A.; M M. C.; Beehler B. C.; Krystek S. R. Jr.; B Y.; Sun C.; Seethala R.; Golla R.; Sleph P. G.; Fura A.; An Y.; Kish K. F.; Sack J. S.; Mookhtiar K. A.; Grover G. J.; Hamann L. G.*Pharmacological and X-ray structural characterization of a novel selective androgen receptor modulator: potent hyperanabolic stimulation of skeletal muscle with hypostimulation of prostate in rats.*Endocrinology*2007,*14814–12. [PubMed]*[Google Scholar]
Gao W.; Bohl C. E.; Dalton J. T.*Chemistry and structural biology of the androgen receptor.*Chem. Rev.*2005,*10593352–3370.*[PMC free article]*[PubMed]*[Google Scholar]
Gao W.; Dalton J. T.*Ockham’s razor and selective androgen receptors (SARMs): Are we overlooking the role of 5α-reductase?.*Mol. Interventions*2007,*7110–13.*[PMC free article]*[PubMed]*[Google Scholar]
pK*data in rats for compound*3*is provided in the*Supporting Information.
Oral data for compounds*3*and*4*in the Herschberger assay is shown in the*Supporting Information.
Human and rat microsome data are shown in the*Supporting Information.
The left-hand side of the molecule as written is presumed to overlay with the A-ring of testosterone. This particular left-hand side equivalent has been utilized to good effect previously in nonsteroidal SARMs:
a.*Li J. J.; Sutton J. C.; Nirschl A.; Zou Y.; Wang H.; Sun C.; Pi Z.; Johnson R.; Krystek S. R. Jr.; Seethala R.; Golla R.; Sleph P. G.; Beehler B. C.; Grover G. J.; Fura A.; Vyas V. P.; Li C. Y.; Gougoutas J. Z.; Galella M. A.; Michael A.; Zahler R.; Ostrowski J.; Hamann L. G.*Discovery of Potent and Muscle Selective Androgen Receptor Modulators through Scaffold Modifications.*J. Med. Chem.*2007,*50133015–3025. The precursor fragment*6*has been described for the preparation of SARMs in: . [PubMed]*[Google Scholar]
b.*Schlienger N.; Lund B. W.; Pawlas J.; Badalassi F.; Bertozzi F.; Lewinsky R.; Fejzic A.; Thygesen M. B.; Tabatabaei A.; Bradley S. R.; Gardell L. R.; Piu F.; Olsson R.*Synthesis, structure−activity relationships, and characterization of novel nonsteroidal and selective androgen receptor modulators.*J. Med. Chem.*2009,*52, 7186–7191. [PubMed]*[Google Scholar]
US2010/0041721.
Wipf P.; Miller C. P.*A new synthesis of highly functionalized oxazoles.*J. Org. Chem.*1993,*58143604–3606.*[Google Scholar]
Johns B. A.; Weatherhead J. G.; Allen S. H.; Thompson J. B.; Garvey E. P.; Foster S. A.; Jeffrey J. L.; Miller W. H.*1,3,4-Oxadiazole substituted naphthyridines as HIV-1 integrase inhibitors. Part 2: SAR of the C5 position.*Biorg. Med. Chem. Lett.*2009,*1961807–1810. [PubMed]*[Google Scholar]
The scheme shown was used to successfully produce approximately 2 kg of compound*5*in >99% purity under GMP manufacturing conditions.
The AR binding assay was performed as specified from the manufacturer. The assay is a fluorometric assay using a tracer made from fluorescent tagged AR-ligand methyltrienolone (R1881).*Ki*values were derived by the Cheng−Prushoff equation (Ki*= (IC50/(1 + /Km)), where*Km*was set equal to*Kd,*Kd*= 25 nM (fluorometric R1881), and = 1.
The C2C12 osteoblast differentiation assay procedure is explained in the*Supporting Information.
Hershberger L. G.; Shipley E. G.; Meyer R. K.*Myotropic activity of 19-nortestosterone and other steroids determined by a modified levator ani muscle method.*Proc. Soc. Exp. Biol. Med.*1953,*83, 175–80. [PubMed]*[Google Scholar]
This dose of TP provides an approximate EC70*on prostate and EC90*on muscle in our Herschberger assays.
RAD140*demonstrated*fairly*linear increases in exposure in male rats up through the 10 mg/kg po dose range, thereby ruling out an exposure limited efficacy as opposed to compound-limited efficacy. Antagonism of TP is further evidence of a mechanism-specific, limited efficacy as opposed to a pharmacokinetic limitation of the compound.
Testosterone levels in castrated rats are
UNCLE Z REP
WWW.UNCLEZ.RU FOR LIST/ORDERING
PM OR EMAIL FOR QUESTIONS/INQUIRIES BUMPMAN82@PROTONMAIL.COM