Non-steroidal antiandrogens: Synthesis and biological profile of high-affinity ligands for the androgen receptor

doi:10.1016/0960-0760(94)90257-7

The Journal of Steroid Biochemistry and Molecular Biology

Volume 48, Issue 1, January 1994, Pages 111-119

https://doi.org/10.1016/0960-0760(94)90257-7 Get rights and content

Abstract

New N-substituted arylthiohydantoin antiandrogens were synthesized. These compounds presented exceptionally high relative binding affinities (RBAs) for the rat androgen receptor (AR): up to 3 times that of testosterone (T) and 100 times the RBAs of non-steroidal antiandrogens such as flutamide, Casodex and Anandron. Furthermore, unlike available markers for AR, they were totally devoid of any binding to the other steroid receptors. RU 59063, the molecule with the highest RBA, was tritiated. When it was compared to [³H]T for the assay of rat, mouse, hamster and AR, it gave rise to the same number of binding sites but its K_a (6×10⁹ M⁻¹) for rat and human AR were, respectively 3 and 8 times higher than that of T. Moreover RU 59063, unlike T, was devoid of any specific binding to human plasma. In vivo, these compounds displayed antiandrogenic activity while being devoid of any agonistic effect. Thus, RU 56187, given orally in castrated male animals, prevented in a dose-dependent manner the effects of 3 mg/kg testosterone propionate (TP) on mouse renal ornithine decarboxylase (acute test) and of 0.5 mg/kg TP on rat prostate weight (chronic test). In these two models, its ED₅₀ was 0.6 and 1 mg/kg, respectively. In the intact rat, when given alone, it inhibited dose-dependently the effect of endogenous androgens on the seminal vesicles (ED₅₀ ≈ 1 mg/kg) and prostate (ED₅₀ ≈ 3 mg/kg) weights. These results suggest that these new compounds may be useful as specific markers for the androgen receptor as well as for the treatment of androgen-dependent diseases or disorders such as prostate cancer, acne, hirsutism and male pattern baldness.

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In this study, the competitive non-steroidal anti-androgen FL442 was further evaluated to estimate its possible therapeutic potential. Since other SHRs, ERα, PR and GR, that play central roles in the regulation of human homeostasis, share common features of structure and function with the AR (Gronemeyer et al., 2004; Huang et al., 2010), synthetic steroidal ligands need to be designed to be specific to the AR over other related receptors in order to prevent cross-reactivity and unwanted side effects (Bohl et al., 2005; Mangelsdorf et al., 1995; Teutsch et al., 1994; Van Dort et al., 2000). The plausible cross-reactivity of FL442 with other SHRs was evaluated in similar assays that were used to study the receptor activity modulation in Ref. Poutiainen et al. (2012), where FL442 at 10 μM concentration inhibited over 90% of the AR activity.
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^☆: This paper is dedicated to Dr Edouard Sakiz, in appreciation of his 40 years of commitment to research in endocrinology.

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PaperNon-steroidal antiandrogens: Synthesis and biological profile of high-affinity ligands for the androgen receptor☆

Abstract

J. Steroid Biochem.

J. Steroid Biochem.

J. Steroid Biochem.

J. Steroid Biochem. Molec. Biol.

J. Steroid Biochem.

Analyt. Biochem.

Analyt. Biochem.

Steroids

J. Steroid Biochem.

J. Steroid Biochem.

J. Steroid Biochem.

J. Steroid Biochem.

Steroids

Pharmacology and potential use of cyproterone acetate

Horm. Metab. Res.

Pharmacology and clinical use of cyproterone acetate

Synandrogenic and antiandrogenic effect of progestins: comparison with non-progestational antiandrogens

Endocrinology

Anti-androgenicity of flutamide and its metabolite Sch 16423

Biochem. Soc. Trans.

The pure antiandrogen RU 23 908 (Anandron)®, a candidate of choice for the combined antihormonal treatment of prostatic cancer: a review

The Prostate

Pharmacology and clinical uses of flutamide

Paper
Non-steroidal antiandrogens: Synthesis and biological profile of high-affinity ligands for the androgen receptor☆