Synthesis and biological evaluation of new fluorine substituted derivatives as angiotensin II receptor antagonists with anti-hypertension and anti-tumor effects

The synthesis and pharmaceutical activity of new potent non-tetrazole angiotensin II (Ang II) receptor antagonists were described. These compounds were fluorine substituted derivatives of Losartan, Valsartan and Irbesartan with carboxylic acid group as replacements to the known potent tetrazole moiety at the 2′-biphenyl position. Their activities were evaluated by Ang II receptor binding assay as well as by in vivo assay. All of the synthesized compounds showed nanomolar affinity for the AT1 receptor subtype. The vivo biological evaluation showed that compounds 1a, 2 and 4 produced a dose-dependent antihypertensive effect both in spontaneously hypertensive rats (SHR) and renal hypertensive rats (RHR). Compound 4 especially showed an efficient and long-lasting effect in reducing blood pressure which can last more than 24 h at dose of 10 mg/kg in SHR, which was much better than control Losartan and Valsartan. Compound 4 can also inhibit the prostate cancer in vitro and in vivo. So compound 4 was selected for in-depth investigation as potent, novel and long-lasting non-tetrazole anti-hypertension and anti-tumor drug candidate.

Compound 4 has a high affinity to AT1 receptor and efficient anti-hypertensive effect. Furthermore, it can inhibit the growth of prostate cancer cells and tumors.Figure optionsDownload as PowerPoint slide