C17,20-lyase inhibitors. Part 2: Design, synthesis and structure–activity relationships of (2-naphthylmethyl)-1H-imidazoles as novel C17,20-lyase inhibitors
| Autor: | Nobuyuki Matsunaga, Masuo Yamaoka, Takahito Hara, Akihiro Tasaka, Toshimasa Tanaka, Tomohiro Kaku, Akio Ojida, Masami Kusaka |
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| Rok vydání: | 2004 |
| Předmět: |
Male
Clinical Biochemistry Lyases Pharmaceutical Science Biochemistry Chemical synthesis Structure-Activity Relationship chemistry.chemical_compound Seminal vesicle Biosynthesis Oral administration Drug Discovery medicine Animals Humans Testosterone Enzyme Inhibitors Molecular Biology chemistry.chemical_classification biology Organic Chemistry Imidazoles Prostate Prostatic Neoplasms Seminal Vesicles Rats Enzyme medicine.anatomical_structure Liver Models Chemical chemistry Enzyme inhibitor biology.protein Molecular Medicine Isopropyl Protein Binding |
| Zdroj: | Bioorganic & Medicinal Chemistry. 12:4313-4336 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2004.06.016 |
| Popis: | 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 C17,20-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. |
| Databáze: | OpenAIRE |
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