Pharmacological profile of RU 58642, a potent systemic antiandrogen for the treatment of androgen-dependent disorders

Battmann, T.; Branche, C.; Bouchoux, F.; Cerede, E.; Philibert, D.; Goubet, F.; Teutsch, G.; Gaillard-Kelly, Martine

doi:10.1016/s0960-0760(97)00151-9

Cited by 21 publications

(18 citation statements)

References 25 publications

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“…In accordance with literature reports (Saksena and Chaudhury, 1970;Teutsch et al, 1994;Battmann et al, 1998), we observed significant decreases in the weights of prostate, seminal vesicles, and levator ani muscle in castrated, vehicle-treated rats (Figs. 2-5).…”

Section: Resultssupporting

confidence: 93%

Pharmacodynamics of Selective Androgen Receptor Modulators

Yin¹,

Gao²,

Kearbey³

et al. 2002

J Pharmacol Exp Ther

138

118

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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 K i 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 (E max ) and dose for half-maximal effect (ED 50 ) 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 ED 50 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.

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Section: Resultssupporting

confidence: 93%

Pharmacodynamics of Selective Androgen Receptor Modulators

Yin¹,

Gao²,

Kearbey³

et al. 2002

J Pharmacol Exp Ther

138

118

View full text Add to dashboard Cite

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“…2A. Consistent with previous literature reports ( Saksena and Chaudhury, 1970;Teutsch et al, 1994;Battmann et al, 1998), castration resulted in a significant reduction in the weights of ventral prostate, seminal vesicles, and levator ani muscle in rats. A subcutaneous dose of TP at 100 g/day increased the weights of ventral prostate, seminal vesicles, and levator ani muscle in castrated animals by 15.4-, 9.3-, and 2.5-fold, respectively.…”

Section: Evaluation Of Pharmacological Activities Of Acetothiolutamidsupporting

confidence: 91%

Pharmacology, Pharmacokinetics, and Metabolism of Acetothiolutamide, a Novel Nonsteroidal Agonist for the Androgen Receptor

Yin¹,

Xu²,

He³

et al. 2002

J Pharmacol Exp Ther

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The present study characterized the in vitro androgen receptor (AR) binding affinity, in vitro and in vivo pharmacological activity, and in vivo pharmacokinetics and metabolism of acetothiolutamide, a nonsteroidal AR ligand. AR binding was determined by a competitive binding assay. In vitro AR agonist activity was examined by a cotransfection assay. Acetothiolutamide displayed high AR binding affinity (K i ϭ 4.9 Ϯ 0.2 nM) and full agonist activity in the in vitro studies. Next, the androgenic, anabolic, and antiandrogenic activity of acetothiolutamide was evaluated in a castrated immature rat model. In this animal model, acetothiolutamide exhibited an overall negligible androgenic effect, but a statistically significant anabolic effect at high subcutaneous doses. Also, acetothiolutamide demonstrated a noticeable antiandrogenic effect in castrated rats supplemented with testosterone propionate. To understand the causes for the observed disparity between in vitro and in vivo activities, pharmacokinetics and metabolism of acetothiolutamide were studied in male Sprague-Dawley rats. Acetothiolutamide was rapidly cleared from rat plasma (clearance of about 45 ml/min/kg) in a concentration-independent manner after i.v. dosing. Acetothiolutamide was completely absorbed after subcutaneous administration, but not bioavailable after oral dose. In the metabolism study, the unchanged molecule and its metabolites in urine and fecal samples were detected by highperformance liquid chromatography-mass spectrometry. The structures of major metabolites were elucidated with liquid chromatography-tandem mass spectrometry. After i.v. administration, acetothiolutamide was excreted in urine and feces as unchanged drug and a variety of metabolites. Oxidation, hydrolysis, and sulfate conjugation of phase I metabolites were the major metabolic pathways of acetothiolutamide in rats. Overall, the high plasma clearance of acetothiolutamide, due to its extensive hepatic metabolism, likely contributed to its lack of androgenic activity in vivo.

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“…On the other hand, Lefort et al (34) showed that bicalutamide treatment does not cause significant decreases in BMD or bone mechanical strength as surgical castration in 16-week old male rats. However, bicalutamide was given at 5 mg/kg/day dose rate through oral gavage, which failed to demonstrate antiandrogen activity in the prostate (35). More importantly, higher incidence of osteoporosis related to androgen deprivation therapy is well recognized clinically.…”

Section: Nonsteroidal Androgen Receptor Antagonistsmentioning

confidence: 99%

“…Topical application not only avoids extensive hepatic metabolism (N-dealkylation) but also provides for effective regional treatment without systemic antiandrogen activity due to the formation of active metabolite (43,44). In comparison, structural analog RU58642 was shown to be orally active (35), and could significantly reduce prostate and seminal vesicle weights in intact male rats at dose rates from 1 to 30 mg/kg/day. It also dramatically increased serum testosterone levels in these animals by blocking the feedback regulation of LH release.…”

Section: Nonsteroidal Androgen Receptor Antagonistsmentioning

confidence: 99%

“…The overall pharmacological profile of this compound is very similar to that of nilutamide. Although RU58642 was more potent than bicalutamide, hydroxyflutamide, and nilutamide, which could be related to its high binding affinity to AR (Table II), no further development of this ligand has been reported since 1998 (35).…”

Section: Nonsteroidal Androgen Receptor Antagonistsmentioning

confidence: 99%

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Pharmacokinetics and Pharmacodynamics of Nonsteroidal Androgen Receptor Ligands

2006

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Testosterone and structurally related anabolic steroids have been used to treat hypogonadism, muscle wasting, osteoporosis, male contraception, cancer cachexia, anemia, and hormone replacement therapy in aging men or age-related frailty; while antiandrogens may be useful for treatment of conditions like acne, alopecia (male-pattern baldness), hirsutism, benign prostatic hyperplasia (BPH) and prostate cancer. However, the undesirable physicochemical and pharmacokinetic properties of steroidal androgen receptor (AR) ligands limited their clinical use. Nonsteroidal AR ligands with improved pharmacological and pharmacokinetic properties have been developed to overcome these problems. This review focuses on the pharmacokinetics, metabolism, and pharmacology of clinically used and emerging nonsteroidal AR ligands, including antagonists, agonists, and selective androgen receptor modulators.

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Pharmacological profile of RU 58642, a potent systemic antiandrogen for the treatment of androgen-dependent disorders

Cited by 21 publications

References 25 publications

Pharmacodynamics of Selective Androgen Receptor Modulators

Pharmacodynamics of Selective Androgen Receptor Modulators

Pharmacology, Pharmacokinetics, and Metabolism of Acetothiolutamide, a Novel Nonsteroidal Agonist for the Androgen Receptor

Pharmacokinetics and Pharmacodynamics of Nonsteroidal Androgen Receptor Ligands

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