Effects of novel 17α-hydroxylase/C17, 20-lyase (P450 17, CYP 17) inhibitors on androgen biosynthesis in vitro and in vivo
Aiming at the development of new drugs for the treatment of prostate cancer, the effects of steroidal compounds and one non-steroidal substance on androgen biosynthesis were evaluated in vitro and in vivo. Sa 40 [17-(5-pyrimidyl)androsta-5,16-diene-3β-ol], its 3-acetyl derivate Sa 41 and BW 19 [3,4-...
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Published in | The Journal of steroid biochemistry and molecular biology Vol. 84; no. 5; pp. 555 - 562 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
Oxford
Elsevier Ltd
01.04.2003
Elsevier Science |
Subjects | |
Online Access | Get full text |
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Summary: | Aiming at the development of new drugs for the treatment of prostate cancer, the effects of steroidal compounds and one non-steroidal substance on androgen biosynthesis were evaluated in vitro and in vivo.
Sa 40 [17-(5-pyrimidyl)androsta-5,16-diene-3β-ol], its 3-acetyl derivate
Sa 41 and
BW 19 [3,4-dihydro-2-(4-imidazolylmethyl)-6-methoxy-1-methyl-naphthalene] are compounds from our group, which have been developed as inhibitors of CYP 17 (17α-hydroxylase-C17, 20-lyase, the key enzyme in androgen biosynthesis). They have been compared with
CB 7598 [abiraterone: 17-(3-pyridyl)androsta-5,16-diene-3β-ol], its 3-acetyl compound
CB 7630 and ketoconazole, compounds which already have been used clinically. The most potent compound toward human CYP 17 (testicular microsomes) was
Sa 40 (IC
50 value of 24
nM), followed by
Sa 41,
CB 7598,
BW 19,
CB 7630 and ketoconazole.
Sa 40 shows a type II difference spectrum and a non-competitive type of inhibition (
K
i
value of 16
nM). No recovery of enzyme activity was observed after preincubation of CYP 17 with
Sa 40 and subsequent charcoal treatment. In
Escherichia coli cells coexpressing human CYP 17 and NADPH-P450 reductase,
Sa 40 was more active than
CB 7598 and
BW 19, whereas the acetyl compounds were not active. The latter three compounds were equally active towards rat CYP 17. Male Sprague–Dawley (SD) rats were administered daily for 14 days
BW 19 and the acetyl derivatives
Sa 41 and
CB 7630 as prodrugs (0.1
mmol/kg intraperitoneally). The test compounds strongly reduced plasma testosterone concentration, as well as prostate and seminal vesicles weights. They showed moderate inhibitory effects on the weights of levator ani, bulbocavernosus and testes, whereas they led to an increase in adrenal and pituitary weights. The only exception was
BW 19 which did not change pituitary weights. Based on its superiority on the human enzyme, it was concluded that
Sa 40 in its 3β-acetate form (
Sa 41) could be a promising candidate for clinical evaluation. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0960-0760 1879-1220 |
DOI: | 10.1016/S0960-0760(03)00070-0 |