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 nM) was identified as a strong
CYP17 inhibitor, showing potent activity in rat, high bioavailability, and a long plasma half-life: 12.8 h.