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The Role of Fluorine Substitution in Biphenyl Methylene Imidazole‐Type CYP17 Inhibitors for the Treatment of Prostate Carcinoma
Author(s) -
Hu Qingzhong,
Negri Matthias,
Olgen Sureyya,
Hartmann Rolf W.
Publication year - 2010
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201000065
Subject(s) - methylene , fluorine , chemistry , trifluoromethyl , in vivo , potency , bioavailability , stereochemistry , pharmacology , imidazole , prostate , in vitro , biochemistry , medicine , medicinal chemistry , organic chemistry , alkyl , biology , microbiology and biotechnology , cancer
It has been established that the growth of most prostate carcinomas depends on androgen stimulation. The inhibition of cytochrome P450‐17 (CYP17) to block androgen biosynthesis is therefore regarded as a promising approach to therapy. Based on our previously identified lead compound Ref 1 , a series of fluorine‐substituted biphenyl methylene imidazoles were designed, synthesized, and evaluated as CYP17 inhibitors to elucidate the influence of fluorine on in vitro and in vivo activity. It was found that meta ‐fluoro substitution at the C ring improved activity, whereas ortho substitution decreased potency. Docking studies performed with our human CYP17 homology model suggest the presence of multipolar interactions between fluorine and Arg109, Lys231, His235, and Glu305. As expected, introduction of fluorine also prolonged the half‐life in plasma. The SARs obtained confirm the reliability of the protein model; compound 9 (IC 50 =131 n M ) was identified as a strong CYP17 inhibitor, showing potent activity in rat, high bioavailability, and a long plasma half‐life: 12.8 h.