C17,20-lyase inhibitors. Part 2: Design, synthesis and structure-activity relationships of (2-naphthylmethyl)-1H-imidazoles as novel C17,20-lyase inhibitors

Nobuyuki Matsunaga, Tomohiro Kaku, Akio Ojida, Toshimasa Tanaka, Takahito Hara, Masuo Yamaoka, Masami Kusaka, Akihiro Tasaka

Research output: Contribution to journalArticle

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Abstract

A series of 1- and 4-(2-naphthylmethyl)-1H-imidazoles (3 and 4) has been synthesized and evaluated as C17,20-lyase inhibitors. Several 6-methoxynaphthyl derivatives showed potent C17,20-lyase inhibition, suppression of testosterone biosynthesis in rats and reduction in the weight of prostate and seminal vesicles in rats, whereas most of these compounds increased the liver weight after consecutive administrations. The effect on the liver weight was removed by incorporation of a hydroxy group and an isopropyl group at the methylene bridge, as seen in (S)-28d and (S)-42. Selectivity for C 17,20-lyase over 11β-hydroxylase is also discussed, and (S)-42 was found to be a more than 260-fold selective inhibitor. Furthermore, (S)-42 showed a potent suppression of testosterone biosynthesis after a single oral administration in monkeys. These data suggest that (S)-42 may be a promising agent for the treatment of androgen-dependent prostate cancer.

Original languageEnglish
Pages (from-to)4313-4336
Number of pages24
JournalBioorganic and Medicinal Chemistry
Volume12
Issue number16
DOIs
Publication statusPublished - Aug 15 2004
Externally publishedYes

Fingerprint

Imidazoles
Lyases
Biosynthesis
Structure-Activity Relationship
Liver
Testosterone
Rats
Steroid 17-alpha-Hydroxylase
Weights and Measures
Seminal Vesicles
Mixed Function Oxygenases
Androgens
Haplorhini
Oral Administration
Weight Loss
Prostate
Prostatic Neoplasms
Derivatives
Therapeutics

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

C17,20-lyase inhibitors. Part 2 : Design, synthesis and structure-activity relationships of (2-naphthylmethyl)-1H-imidazoles as novel C17,20-lyase inhibitors. / Matsunaga, Nobuyuki; Kaku, Tomohiro; Ojida, Akio; Tanaka, Toshimasa; Hara, Takahito; Yamaoka, Masuo; Kusaka, Masami; Tasaka, Akihiro.

In: Bioorganic and Medicinal Chemistry, Vol. 12, No. 16, 15.08.2004, p. 4313-4336.

Research output: Contribution to journalArticle

Matsunaga, Nobuyuki ; Kaku, Tomohiro ; Ojida, Akio ; Tanaka, Toshimasa ; Hara, Takahito ; Yamaoka, Masuo ; Kusaka, Masami ; Tasaka, Akihiro. / C17,20-lyase inhibitors. Part 2 : Design, synthesis and structure-activity relationships of (2-naphthylmethyl)-1H-imidazoles as novel C17,20-lyase inhibitors. In: Bioorganic and Medicinal Chemistry. 2004 ; Vol. 12, No. 16. pp. 4313-4336.
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