Nonsteroidal Selective Androgen Receptor Modulators (SARMs): Dissociating the Anabolic and Androgenic Activities of the Androgen Receptor for Therapeutic Benefit

Mohler, Michael L.; Bohl, Casey E.; Jones, Amanda; Coss, Christopher C.; Narayanan, Ramesh; He, Yu‐Ying; Hwang, Dong-Jin; Dalton, James T.; Miller, Duane D.

doi:10.1021/jm900280m

Cited by 183 publications

(146 citation statements)

References 160 publications

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“…There may be long-term issues with the use of these compounds due to lack of conversion to aromatic A-ring metabolites 53 and possible effects on lipid metabolism. There are also a number of non-steroidal selective androgen receptor modulators that are in development [54][55][56] for androgen replacement and treatment of sarcopenia. There are other non-steroidal selective androgen receptor modulators that possess both androgen and progestational activities that may be effective in suppressing gonadotropins, maintaining androgenic actions, but sparing the stimulatory effect on the prostate gland while the effects on lipids and long-term cardiovascular health are not known.…”

Section: Resultsmentioning

confidence: 99%

Does ethnicity matter in male hormonal contraceptive efficacy?

Ilani¹,

Liu²,

Swerdloff³

et al. 2011

Asian J Androl

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The development of male hormonal contraception has progressed significantly during the last three decades. The ultimate goal is to produce an effective, safe and reversible male method of contraception that are within reach of and can be used by all men globally. This review aims to outline the recent developments in male hormonal contraception with special emphasis on how ethnicity influences acceptability, extent of sperm suppression, and rate of recovery of spermatogenesis. Baseline differences in testicular histomorphology and testosterone metabolism between East Asian and Caucasian men have been reported, but whether this contributes significantly to varying degrees of sperm suppression in response to exogenous testosterone therapy is less known. Testosterone alone male hormonal contraceptive regimens are effective and applicable for East Asian men, and less so for Caucasians. Combinations of progestins with androgens are sufficient to optimize effectiveness of suppression and applicability to all ethnicities. New compounds such as steroidal or non-steroidal selective androgen receptor modulators with dual androgenic and progestational activities are potential compounds for further development as male hormonal contraceptive methods. At the present time, combined androgen and progestin contraceptive regimens appear to be effective, safe, reversible and convenient to use for all men with ethnic, cultural and environmental differences. Further refinements on the hormonal agent, methods of delivery, and dose optimization of the androgen relative to the progestin are necessary. This goal mandates further investment and large clinical trials in multiethnic populations to better define safety and efficacy.

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Section: Resultsmentioning

confidence: 99%

Does ethnicity matter in male hormonal contraceptive efficacy?

Ilani¹,

Liu²,

Swerdloff³

et al. 2011

Asian J Androl

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“…Several estrogenic chemicals, among others flavonoids and resveratrol, have been shown to interact not only with ERs, but also with aryl hydrocarbon receptor (AhR) (Revel et al, 2003;Van der Heiden, et al, 2009). Antiandrogens, such as flutamide, vinclozolin, prochloraz and linuron, repress ARmediated transcriptional activation, by competitive inhibition of endogenous androgens binding to their receptor Lambright et al, 2000;Mohler et al, 2009;Noriega et al, 2005;Vinggaard et al, 2002). Binding of antiandrogen may result in a conformational change of ligand binding domain of AR appropriate for the interaction with co-repressors, instead of coactivators (Berrevoets et al, 2002;Hodgson et al, 2008).…”

Section: Interaction With Hormone Receptorsmentioning

confidence: 99%

Antiandrogenic and Estrogenic Compounds: Effect on Development and Function of Male Reproductive System

Hejmej¹,

Kotula–Balak²,

Bilińska³

2011

Steroids - Clinical Aspect

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“…12 We now present our initial characterization of the antischistosomal versus antiandrogenic properties of these four aryl hydantoins.…”

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confidence: 99%

“…The binding competition observed for nilutamide and AH03 is consistent with previous data showing that AR ligands with aryl nitro or nitrile functional groups can form ion-dipole interactions with R752 in the AR ligand-binding domain. 12 To put the AR ligand competition data in context, we assessed the effects of the aryl hydantoins on androgendependent LNCaP C-33 human prostate cancer cells.…”

mentioning

confidence: 99%

Antischistosomal versus Antiandrogenic Properties of Aryl Hydantoin Ro 13-3978

Wang¹,

Zhao²,

Min³

et al. 2014

The American Society of Tropical Medicine and Hygiene

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Abstract. In the early 1980s, the antischistosomal aryl hydantoin Ro 13-3978 (AH01), a close structural analogue of the androgen receptor antagonist nilutamide, was discovered. Administration of 100 mg/kg oral doses of AH01 to mice infected with adult and juvenile Schistosoma mansoni produced 95% and 64% total worm burden reductions, confirming its high activity against adult worms, and showing that AH01 is also effective against juvenile infections. AH01 had no measureable interaction with the androgen receptor in a ligand competition assay, but it did block dihydrotestosteroneinduced cell proliferation in an androgen-dependent human prostate cancer cell line. For AH01, nilutamide, and three closely related aryl hydantoin derivatives, there was no correlation between antischistosomal activity and androgen receptor interaction.Schistosomiasis is a neglected but widespread tropical disease caused by infection with parasitic blood flukes. Schistosoma mansoni, Schistosoma haematobium, and Schistosoma japonicum are the most widely distributed species and cause the highest disease burden, particularly in sub-Saharan Africa.1-3 Praziquantel (PZ) is the only drug available for treatment of this disease, and it is active against adult schistosomes, but has little activity against the juvenile schistosomula, the young developmental stages of the parasite.2,4 Should serious praziquantel drug resistance arise, there are no viable alternatives to this drug. Even so, drug discovery for schistosomiasis has languished.The introduction of PZ in 1982 likely led to decisions to abandon the development of a number of promising antischistosomal agents that were discovered in the same time period. One of these was Ro 13-3978 (AH01), the lead compound from a series of aryl hydantoins that were investigated in some detail at Hoffmann La-Roche.5-8 A number of these aryl hydantoins had high oral efficacy in schistosome animal models, 8 but they also produced antiandrogenic side effects in the host, 5 a not unexpected outcome given the close structural similarity of these aryl hydantoins to the antiandrogenic drug nilutamide (Figure 1). We recently showed 9 that nilutamide, but not the three structurally diverse androgen receptor (AR) antagonists flutamide, bicalutamide, and cyproterone acetate, has antischistosomal activity. As phylogenetic evidence indicates that schistosome species do not appear to have ARs, 10 the data led us to hypothesize that for aryl hydantoins and related heterocycles, the structural requirements for antischistosomal efficacy and AR binding interactions are divergent.Based on the limited elucidation of the structureactivity-relationship of this aryl hydantoin compound series, 8 we began to test this hypothesis by the synthesis 8,11 of AH01, its imino isostere AH02, and two derivatives (AH03 and AH04) incorporating nitrile functional groups (present in bicalutamide and other antiandrogens) known to import high AR binding affinity. 12 We now present our initial characterization of the antischistosomal versus antia...

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Nonsteroidal Selective Androgen Receptor Modulators (SARMs): Dissociating the Anabolic and Androgenic Activities of the Androgen Receptor for Therapeutic Benefit

Abstract: propionate; tP t , twitch time to peak tension; t 1/2 R, twitch recovery time; TRT, testosterone replacement therapy; VP, ventral prostate; V ss , volume of distribution at steady state; wt, wild type.

Cited by 183 publications

References 160 publications

Does ethnicity matter in male hormonal contraceptive efficacy?

Does ethnicity matter in male hormonal contraceptive efficacy?

Antiandrogenic and Estrogenic Compounds: Effect on Development and Function of Male Reproductive System

Antischistosomal versus Antiandrogenic Properties of Aryl Hydantoin Ro 13-3978

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