Chapter 21. New Horizons in the Treatment of Proliferative Prostatic Disease

Mallamo, John P.; Juniewicz, P. E.

doi:10.1016/s0065-7743(08)60543-6

Cited by 4 publications

(1 citation statement)

References 107 publications

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“…There are a number of pharmacological approaches being sought for the above diseases. These include inhibition of the conversion of testosterone to dihydrotestosterone by inhibiting 5a-reductase by a series of 4-aza steroids,2-4 inhibition of androgen production by LHRH agonists,5 inhibition of androgen action by androgen receptor antagonists, and inhibition of the transformation of androgens to estrogens by aromatase inhibitors.1 In addition to these steroidal antagonists, nonsteroidal antiandrogens such as hydroxyflutamide (1) and bicalutamide (Casodex, 2) which lack the hormonal agonist activity have been reported.6 '7 We are interested in the androgen receptor-based approach to androgen regulation and recently described the novel antiandrogens steroidal (methylsulfonyl)pyrazole (Zan-of the steroid nucleus, the position occupied by the oxygen of the natural ligand dihydrotestosterone, carries a partial negative charge to attain androgen receptor affinity. Thus, the bioisosteric replacement of (methylsulfonyl)pyrazole with other methylsulfonyl heterocycles also resulted in the androgen receptor affinity and the androgen antagonist activity.10 It appears that in these series of compounds the appropriately substituted A-ring-fused heterocycles with a methysulfonyl group and C-17a substitution were an optimal combination for androgen receptor binding and in vivo antiandrogenic potency.…”

Section: Introductionmentioning

confidence: 99%

Androgen Receptor Affinity of 5'-Acyl Furanosteroids

Kumar

Ackerman²,

Alexander³

et al. 1994

J. Med. Chem.

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Syntheses of 5'-acyl furanosteroids are described from the corresponding unsubstituted [3,2-b]furanosteroids using acid anhydrides and acid chlorides in the presence or absence of Lewis acids. New methods have been developed to prepare 5'-acetyl derivatives: reduction of a 5'-trichloroacetyl intermediate either by sodium formaldehyde sulfoxylate or with 10% Pd/C. Most of these 5'-acyl derivatives bind to the rat ventral prostate androgen receptor. However the antiandrogenic activity was diminished when compared with 4,5'-methylsulfonyl furanosteroid. Biological studies revealed that 5'-acyl furanosteroids were either androgens or modest antiandrogens. The electrostatic potential maps of the substructures of 3, 4, and 5'-acetyl syn- and anti-furanosteroids showed striking differences which may explain, to some extent, the lack of significant antiandrogenic activity of 5'-acyl furanosteroids.

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Section: Introductionmentioning

confidence: 99%

Androgen Receptor Affinity of 5'-Acyl Furanosteroids

Kumar

Ackerman²,

Alexander³

et al. 1994

J. Med. Chem.

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Effects of androgen and antiandrogen treatment on canine prostatic arginine esterase

et al. 1990

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A series of experiments were conducted to investigate the regulation of the primary secretory protein of the canine prostate, arginine esterase, by androgens and/or new antiandrogen under development. In the first experiment, castration decreased (P less than 0.05) prostatic arginine esterase levels relative to intact controls (0.26 +/- 0.1 and 17.0 +/- 0.1 mumole/min/mg protein, respectively). Treatment of castrate dogs with either 5, 10, or 20 silastic capsules (8 cm length) containing the androgen 5 alpha-androstane-3 alpha, 17 beta-diol (3 alpha-diol) plus 1 capsule containing estradiol-17 beta (E2) or the i.m. injection of 25 mg 3 alpha-diol and 0.25 mg E2 for 12 weeks resulted in a dose-dependent increase (P less than 0.05) in prostatic arginine esterase activity (6.8 +/- 1.7, 19.0 +/- 3.6, 21.3 +/- 0.9, and 14.2 +/- 0.7 mumole/min/mg protein, respectively). In the second experiment, steroid treatment (10 3 alpha-diol plus 1 E2 silastic capsules) of castrate dogs for 12 weeks resulted in prostatic arginine esterase activity of 17.8 +/- 2.3 mu mole/min/mg. Co-administration of the steroidal androgen receptor antagonist. Win 49,596 (WIN) at doses of 0.625, 2.5, 10, or 40 mg/kg/day p.o., dose-dependently inhibited (P less than 0.05) prostatic arginine esterase activity (14.9 +/- 1.1, 14.3 +/- 1.3, 3.4 +/- 1.9, and 0.21 +/- 0.1 mumole/min/mg, respectively) to levels similar to that observed in castrate controls (0.14 +/- 0.03 mumole/min/mg). Administration of the nonsteroidal androgen receptor antagonist flutamide at 10 mg/kg/day p.o. to steroid-induced dogs also inhibited (P less than 0.05) arginine esterase activity (0.07 +/- 0.02 mumole/min/mg). In the last experiment, treatment of intact dogs with WIN at 0.625, 2.5, 10, and 40 mg/kg/day for 16 weeks dose-dependently reduced (P less than 0.05) arginine esterase levels (17.0 +/- 1.0, 16.3 +/- 1.5, 10.2 +/- 1.2, and 3.9 +/- 2.5 mumole/min/mg, respectively) compared to intact controls (14.4 +/- 1.2 mumole/min/mg). Histomorphologic and ultrastructural evaluation of prostates from dogs indicated that antiandrogen treatment resulted in glandular epithelial atrophy as well as a reduction in the number of secretory granules. The results of these experiments support that canine prostatic arginine esterase activity is under androgenic control, can be inhibited by antiandrogen treatment and may serve as a functional marker of the androgenic state of the prostate. Whether the effects of androgen and antiandrogens on prostatic arginine esterase is direct or indirect due to a general inhibitory effect on secretory epithelial cell function requires additional study. Furthermore, subject to further evaluation, the steroidal androgen receptor antagonist.(ABSTRACT TRUNCATED AT 400 WORDS)

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Chapter 23. Therapeutic Control of Androgen Action

Rasmusson

Toney

1994

Annual Reports in Medicinal Chemistry

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Chapter 21. New Horizons in the Treatment of Proliferative Prostatic Disease

Cited by 4 publications

References 107 publications

Androgen Receptor Affinity of 5'-Acyl Furanosteroids

Androgen Receptor Affinity of 5'-Acyl Furanosteroids

Effects of androgen and antiandrogen treatment on canine prostatic arginine esterase

Chapter 23. Therapeutic Control of Androgen Action

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