17,20-Lyase inhibitors. Part 3: Design, synthesis, and structure–activity relationships of biphenylylmethylimidazole derivatives as novel 17,20-lyase inhibitors

• Published in: Bioorganic & medicinal chemistry Vol. 19; no. 7; pp. 2428 - 2442
• Main Authors: Kaku, Tomohiro, Tsujimoto, Saori, Matsunaga, Nobuyuki, Tanaka, Toshimasa, Hara, Takahito, Yamaoka, Masuo, Kusaka, Masami, Tasaka, Akihiro
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.04.2011; Elsevier
• Subjects: 17,20-Lyase; Animals; Biological and medical sciences; biphenyl; blood serum; Crystallography, X-Ray; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; DHEA; enantiomers; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; high performance liquid chromatography; Humans; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Inhibitory Concentration 50; Macaca fascicularis; Male; Medical sciences; Models, Molecular; monkeys; oral administration; Pharmacology. Drug treatments; prasterone; Prostate cancer; Rats; Rats, Sprague-Dawley; Steroid 17-alpha-Hydroxylase - antagonists & inhibitors; steroid hormones; Structure-Activity Relationship; structure-activity relationships; Testosterone; Urinary system; X-ray diffraction; DHEA; Testosterone; 17,20-Lyase; Prostate cancer; Imidazole derivatives; Rat; Monkey; Steroid 17α-monooxygenase; Antihormone; Structure activity relation; Tertiary alcohol; Primates; Chemical synthesis; Non steroid compound; Human; Enzyme; Rodentia; Oral administration; Enzyme inhibitor; Antiandrogen; In vitro; In vivo; Vertebrata; Dehydroepiandrosterone; Mammalia; Biphenyl derivatives; Animal; Carboxamide; Oxidoreductases
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2011.02.009

A novel series of biphenylylmethylimidazole derivatives were synthesized as inhibitors of 17,20-lyase, and their biological activities were evaluated. A novel series of biphenylylmethylimidazole derivatives and related compounds were synthesized as inhibitors of 17,20-lyase, a key enzyme in the production of steroid hormones, and their biological activities were evaluated. In an attempt to identify potent and selective inhibitors of 17,20-lyase over the related CYP3A4 enzyme, a homology model for human 17,20-lyase was developed using the X-ray crystallographic structure of the mammalian CYP2C5 enzyme. With the aid of molecular modeling, optimization of the biphenyl moiety was performed to give an acetamide derivative, which was resolved by HPLC to give the active (−)-enantiomer. The obtained active enantiomer showed not only potent inhibition of both rat and human 17,20-lyase,with IC 50 values of 14 and 26 nM, respectively, but also excellent selectivity (>300-fold) for inhibition of 17,20-lyase over CYP3A4. Moreover, the active enantiomer significantly reduced both serum testosterone and DHEA concentrations in a monkey model after single oral administration. Asymmetric synthesis of the active enantiomer was also developed via a chiral intermediate using a diastereoselective Grignard reaction.