The role of fluorine substitution in biphenyl methylene imidazole-type CYP17 inhibitors for the treatment of prostate carcinoma.
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.
Hu
Qingzhong
Q
Pharmaceutical and Medicinal Chemistry, Saarland University, PO Box 151150 & Helmholtz Institute for Pharmaceutical Research, Saarland HIPS, 66041 Saarbrücken, Germany.
Negri
Matthias
M
Olgen
Sureyya
S
Hartmann
Rolf W
RW
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000737:chemistry*; D002277:Carcinoma / Q000188:drug therapy*; D003198:Computer Simulation; D015195:Drug Design; D005461:Fluorine / Q000737:chemistry*; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D005461:Fluorine; D007093:Imidazoles; D013254:Steroid 17-alpha-Hydroxylase; C010574:biphenyl