![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Vol. 304, Issue 3, 1334-1340, March 2003
Division of Pharmaceutics and Pharmaceutical Chemistry, College of
Pharmacy, The Ohio State University, Columbus, Ohio (D.Y., W.G.,
J.D.K., H.X., J.T.D.); Department of Pharmaceutical Sciences, College
of Pharmacy, University of Tennessee, Memphis, Tennessee (K.C., Y.H.,
C.A.M., D.D.M.); and GTx, Inc., Memphis, Tennessee (K.A.V.)
The present study aimed to identify selective androgen receptor
modulators (SARMs) with in vivo pharmacological activity. We examined
the in vitro and in vivo pharmacological activity of four chiral,
nonsteroidal SARMs synthesized in our laboratories. In the in vitro
assays, these compounds demonstrated moderate to high androgen receptor
(AR) binding affinity, with Ki values ranging from 4 to 37 nM, and three of the compounds efficaciously stimulated AR-mediated reporter gene expression. The compounds were
then administered subcutaneously to castrated rats to appraise their in
vivo pharmacological activity. Androgenic activity was evaluated by the
ability of these compounds to maintain the weights of prostate and
seminal vesicle, whereas levator ani muscle weight was used as a
measure of anabolic activity. The maximal response (Emax) and dose for half-maximal effect
(ED50) were determined for each compound and compared with
that observed for testosterone propionate (TP). Compounds S-1 and S-4
demonstrated in vivo androgenic and anabolic activity, whereas
compounds S-2 and S-3 did not. The activities of S-1 and S-4 were
tissue-selective in that both compounds stimulated the anabolic organs
more than the androgenic organs. These two compounds were less potent
and efficacious than TP in androgenic activity, but their anabolic
activity was similar to or greater than that of TP. Neither S-1 nor S-4
caused significant luteinizing hormone or follicle stimulating
hormone suppression at doses near the ED50 value.
Thus, compounds S-1 and S-4 were identified as SARMs with potent and
tissue-selective in vivo pharmacological activity, and represent the
first members of a new class of SARMs with selective anabolic effects.
This article has been cited by other articles:
|
|
 |
|
  W. Gao and J. T. Dalton Ockham's Razor and Selective Androgen Receptor Modulators (SARMs): Are We Overlooking the Role of 5{alpha}-Reductase? Mol. Interv., February 1, 2007; 7(1): 10 - 13. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Z. Lu, S. E. Wardell, K. L. Burnstein, D. Defranco, P. J. Fuller, V. Giguere, R. B. Hochberg, L. McKay, J.-M. Renoir, N. L. Weigel, et al. International Union of Pharmacology. LXV. The Pharmacology and Classification of the Nuclear Receptor Superfamily: Glucocorticoid, Mineralocorticoid, Progesterone, and Androgen Receptors Pharmacol. Rev., December 1, 2006; 58(4): 782 - 797. [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Perera, D. Yin, D. Wu, K. K. Chan, D. D. Miller, and J. Dalton In Vivo Metabolism and Final Disposition of a Novel Nonsteroidal Androgen in Rats and Dogs Drug Metab. Dispos., October 1, 2006; 34(10): 1713 - 1721. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Dehm and D. J. Tindall Ligand-independent Androgen Receptor Activity Is Activation Function-2-independent and Resistant to Antiandrogens in Androgen Refractory Prostate Cancer Cells J. Biol. Chem., September 22, 2006; 281(38): 27882 - 27893. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.-M. Axell, H. E. MacLean, D. R. Plant, L. J. Harcourt, J. A. Davis, M. Jimenez, D. J. Handelsman, G. S. Lynch, and J. D. Zajac Continuous testosterone administration prevents skeletal muscle atrophy and enhances resistance to fatigue in orchidectomized male mice Am J Physiol Endocrinol Metab, September 1, 2006; 291(3): E506 - E516. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Yang, C. E. Bohl, V. A. Nair, S. M. Mustafa, S. S. Hong, D. D. Miller, and J. T. Dalton Preclinical Pharmacology of a Nonsteroidal Ligand for Androgen Receptor-Mediated Imaging of Prostate Cancer J. Pharmacol. Exp. Ther., April 1, 2006; 317(1): 402 - 408. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Wu, Z. Wu, J. Yang, V. A. Nair, D. D. Miller, and J. T. Dalton PHARMACOKINETICS AND METABOLISM OF A SELECTIVE ANDROGEN RECEPTOR MODULATOR IN RATS: IMPLICATION OF MOLECULAR PROPERTIES AND INTENSIVE METABOLIC PROFILE TO INVESTIGATE IDEAL PHARMACOKINETIC CHARACTERISTICS OF A PROPANAMIDE IN PRECLINICAL STUDY Drug Metab. Dispos., March 1, 2006; 34(3): 483 - 494. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Gao, Z. Wu, C. E. Bohl, J. Yang, D. D. Miller, and J. T. Dalton CHARACTERIZATION OF THE IN VITRO METABOLISM OF SELECTIVE ANDROGEN RECEPTOR MODULATOR USING HUMAN, RAT, AND DOG LIVER ENZYME PREPARATIONS Drug Metab. Dispos., February 1, 2006; 34(2): 243 - 253. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Gao, J. S. Johnston, D. D. Miller, and J. T. Dalton INTERSPECIES DIFFERENCES IN PHARMACOKINETICS AND METABOLISM OF S-3-(4-ACETYLAMINO-PHENOXY)-2-HYDROXY-2-METHYL-N-(4-NITRO-3-TRIFLUOROMETHYLPHENYL)-PROPIONAMIDE: THE ROLE OF N-ACETYLTRANSFERASE Drug Metab. Dispos., February 1, 2006; 34(2): 254 - 260. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Chen, D. J. Hwang, K. Chung, C. E. Bohl, S. J. Fisher, D. D. Miller, and J. T. Dalton In Vitro and in Vivo Structure-Activity Relationships of Novel Androgen Receptor Ligands with Multiple Substituents in the B-Ring Endocrinology, December 1, 2005; 146(12): 5444 - 5454. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Gao, P. J. Reiser, C. C. Coss, M. A. Phelps, J. D. Kearbey, D. D. Miller, and J. T. Dalton Selective Androgen Receptor Modulator Treatment Improves Muscle Strength and Body Composition and Prevents Bone Loss in Orchidectomized Rats Endocrinology, November 1, 2005; 146(11): 4887 - 4897. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Kim, D. Wu, D. J. Hwang, D. D. Miller, and J. T. Dalton 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. Exp. Ther., October 1, 2005; 315(1): 230 - 239. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Chen, J. D Zajac, and H. E MacLean Androgen regulation of satellite cell function J. Endocrinol., July 1, 2005; 186(1): 21 - 31. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Chen, J. Kim, and J. T. Dalton Discovery and Therapeutic Promise of Selective Androgen Receptor Modulators Mol. Interv., June 1, 2005; 5(3): 173 - 188. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Chen, D. J. Hwang, C. E. Bohl, D. D. Miller, and J. T. Dalton A Selective Androgen Receptor Modulator for Hormonal Male Contraception J. Pharmacol. Exp. Ther., February 1, 2005; 312(2): 546 - 553. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Y. Liu, R. C. Christian, M. Ruan, V. M. Miller, and L. A. Fitzpatrick Correlating Androgen and Estrogen Steroid Receptor Expression with Coronary Calcification and Atherosclerosis in Men without Known Coronary Artery Disease J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 1041 - 1046. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. R. Brown Nonsteroidal Selective Androgen Receptors Modulators (SARMs): Designer Androgens with Flexible Structures Provide Clinical Promise Endocrinology, December 1, 2004; 145(12): 5417 - 5419. [Full Text] [PDF]
|
|
|
|
|
|
W. Gao, J. D. Kearbey, V. A. Nair, K. Chung, A. F. Parlow, D. D. Miller, and J. T. Dalton Comparison of the Pharmacological Effects of a Novel Selective Androgen Receptor Modulator, the 5{alpha}-Reductase Inhibitor Finasteride, and the Antiandrogen Hydroxyflutamide in Intact Rats: New Approach for Benign Prostate Hyperplasia Endocrinology, December 1, 2004; 145(12): 5420 - 5428. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Y. Liu, R. S. Swerdloff, and J. D. Veldhuis The Rationale, Efficacy and Safety of Androgen Therapy in Older Men: Future Research and Current Practice Recommendations J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 4789 - 4796. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
