Journal of Medicinal Chemistry
Brief Article
(14) Hazzard, W. R.; Wahl, P. W.; Gagne, C.; Applebaum-Bowden,
D.; Warnick, G. R.; Albers, J. J. Plasma and lipoprotein lipid responses
to four hypolipid drugs. Lipids 1984, 19, 73−79.
(15) Xu, L.; Freeman, G.; Cowling, B. J.; Schooling, C. M.
Testosterone therapy and cardiovascular events among men: A
systematic review and meta-analysis of plcebo-controlled randomized
trials. BMC Med. 2013, 11, 108−120.
(16) Ullrich, T.; Sasmal, S.; Boorgu, V.; Pasagadi, S.; Cheera, S.;
Rajagopalan, S.; Bhumireddy, A.; Shashikumar, D.; Chelur, S.;
Belliappa, C.; Pandit, C.; Krishnamurthy, N.; Mukherjee, S.;
Ramanathan, A.; Ghadiyaram, C.; Ramachandra, M.; Santos, P. G.;
Lagu, B.; Bock, M. G.; Perrone, M. H.; Weiler, S.; Keller, H. 3-Alkoxy-
pyrrolo[1,2-b]pyrazolines as selective androgen receptor modulators
with idea physiochemical properties for transdermal administration. J.
Med. Chem. 2014, 57, 7396−7411.
(17) Bos, J. D.; Meinardi, M. M. H. M. 500 Da rule for the skin
penetration of chemical compounds and drugs. Exp. Dermatol. 2000, 9,
165−169.
(18) Hadgraft, J.; Guy, R. H. Feasibility assessment in topical and
transdermal delivery: mathematical models and in-vitro studies. In
Transdermal Drug Delivery, 2nd ed.; Guy, R. H., Hadgraft, J., Eds.;
Marcel Dekker Inc.: New York, 2002; pp 1−23.
(19) Potts, R. O.; Guy, R. H. Predicting skin permeability. Pharm.
Res. 1992, 9, 663−669.
(20) Jadhav, P. K.; Saeed, A.; Green, J. E.; Krishnan, V.; Matthews, D.
P.; Stephenson, G. A. Selective androgen receptor modulators. WO
2013/055577 A1, April 18, 2013.
(21) Weingand, K. W. Atherosclerosis research in cynomolgus
monkeys. Exp. Mol. Pathol. 1989, 50, 1−15.
(22) Winegar, D. A.; Brown, P. J.; Wilkison, W. O.; Lewis, M. C.; Ott,
R. J.; Tong, W. Q.; Brown, H. R.; Lehman, J. M.; Kliewer, S. A.;
Plunket, K. L.; Way, J. M.; Bodkin, N. L.; Hansen, B. C. Effect of
fenofibrate on lipid parameters in obese rhesus monkeys. J. Lipid Res.
2001, 42, 1543−1551.
Michael Grogan for their scientific input and review of the
manuscript. This research used resources of the Advanced
Photon Source, a U.S. Department of Energy (DOE) Office of
Science User Facility operated for the DOE Office of Science
by Argonne National Laboratory under contract no. DE-AC02-
06CH11357. Use of the Lilly Research Laboratories Collabo-
rative Access Team (LRL-CAT) beamline at Sector 31 of the
Advanced Photon Source was provided by Eli Lilly Company,
which operates the facility.
ABBREVIATIONS USED
■
AR androgen receptor; ER estrogen receptor; PR progesterone
receptor; GR glucocorticoid receptor, and MR mineralocorti-
coid receptor; SARM selective androgen receptor modulators
REFERENCES
■
(1) 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, 58, 782−
797.
(2) Lee, N. K.; MacLean, H. E. Polyamines, androgens, and skeletal
muscle hypertrophy. J. Cell. Physiol. 2011, 226, 1453−1460.
(3) Dillon, E. L.; Durham, W. J.; Urban, R. J.; Sheffield-Moore, M.
Hormone treatment and muscle anabolism during aging: androgens.
Clin. Nutr. 2010, 29, 697−700.
(4) Gelman, E. P. Molecular biology of the androgen receptor. J. Clin.
Oncol. 2002, 20, 3001−3015.
(5) Basaria, S.; Coviello, A. D.; Travison, T. G.; Storer, T. W.;
Farwell, W. R.; Jette, A. M.; Eder, R.; Tennstedt, S.; Ulloor, J.; Zhang,
A.; Choong, K.; Lakshman, K. M.; Mazer, N. A.; Miciek, R.; Krasnoff,
J.; Elmi, A.; Knapp, P. E.; Brooks, B.; Appleman, E.; Aggarwal, S.;
Bhasin, G.; Hede-Brierley, L.; Bhatia, A.; Collins, L.; LeBrasseur, N.;
Fiore, L. D.; Bhasin, S. Adverse events associated with testosterone
administration. N. Engl. J. Med. 2010, 363, 109−122.
(6) Mohler, M. L.; Bohl, C. E.; Jones, A.; Coss, C. C.; Narayanan, R.;
He, Y.; Hwang, D. J.; Dalton, J. T.; Miller, D. D. Nonsteroidal selective
androgen receptor modulators (SARMs): Dissociating the anabolic
and androgenic activities of the androgen receptor for therapeutic
benefit. J. Med. Chem. 2009, 52, 3597−3617.
(7) Dalton, J. T.; Barnette, K. G.; Bohl, C. E.; Hancock, M. L.;
Rodriguez, D.; Dodson, S. T.; Morton, R. A.; Steiner, M. S. The
selective androgen receptor modulator GTx-024 (enobosarm)
improves lean body mass and physical function in healthy elderly
men and postmenopausal women: Results of double blinded, placebo-
controlled phase II trial. J. Cachexia Sarcopenia Muscle 2011, 2, 153−
161.
(8) Gao, W.; Bohl, C. E.; Dalton, J. T. Chemistry and structural
biology of the androgen receptor. Chem. Rev. 2005, 105, 3352−3370.
(9) 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.
(10) Schleich, F.; Legros, J. Effects of Androgen substitution on lipid
profile in the adult and aging hypogonadal male. Eur. J. Endocrinol.
2004, 151, 415−424.
(11) Eckardstein, V. A.; Wu, F. C. W. Testosterone and
atherosclerosis. Growth Horm. IGF Res. 2003, 13, S72−S84.
(12) Liu, P. Y.; Death, A. K.; Handelsman, D. J. Androgens and
cardiovascular disease. Endocr. Rev. 2003, 24, 313−340.
(13) Thompson, P. D.; Cullinane, E. M.; Sady, S. P.; Chnevert, C.;
Saritelli, A. L.; Sady, M. A.; Herbert, P. N. Contrasting effects of
testosterone and stanozolol on serum lipoprotein levels. JAMA, J. Am.
Med. Assoc. 1989, 261, 1165−1168.
F
J. Med. Chem. XXXX, XXX, XXX−XXX