Synthesis and Biological Evaluation of a New Angiotensin II Receptor Antagonist

H.-l. Zheng; W.-b. Zhu; D. Wu; Y.-j. Da; Y.-J. Yan; J. Bian; Z.-l. Chen

doi:10.1055/s-0034-1367075

Drug Research, Table of Contents

Drug Res (Stuttg) 2014; 64(12): 656-662
DOI: 10.1055/s-0034-1367075

Original Article

Synthesis and Biological Evaluation of a New Angiotensin II Receptor Antagonist

H.-l. Zheng

¹Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, Shanghai, China

,

W.-b. Zhu

¹Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, Shanghai, China

,

D. Wu

¹Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, Shanghai, China

,

Y.-j. Da

¹Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, Shanghai, China

,

Y.-J. Yan

¹Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, Shanghai, China

,

J. Bian

¹Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, Shanghai, China

,

Z.-l. Chen

¹Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, Shanghai, China

› Author Affiliations

Abstract

The design, synthesis, in vitro and in vivo evaluation of (2 R,6 S)-4-({1-[2-(1 H-tetrazol-5-yl)phenyl]-1 H-indol-4-yl}methyl)-2,6-dimethylmorpholine, compound 1, as a novel angiotensin II receptor antagonist is outlined. Radioligand binding assays showed that 1 displayed a high affinity for the angiotensin II type 1receptor with IC₅₀ value of 0.82 nM. It acted as a potent anti-hypertensive derivative (maximal reduction of mean arterial pressure of 47 mm Hg at 10 mg/kg po in spontaneously hypertensive rat producing a dose-dependent fall in blood pressure following oral administration lasting beyond 10 h. Acute toxicity tests measured the LD₅₀ of 1 value as 2431.7 mg/kg, which is higher than Losartan (LD₅₀=2248 mg/kg). In addition further testing showed that 1 also demonstrated efficient anti-proliferative activity in vitro and anti-prostate cancer activity in vivo were also found. Taken together this compound could be considered as an effective and durable anti-hypertension drug candidate with additional anti-prostate cancer activity. These encouraging results are deserved of further investigation towards its use for therapeutic benefit.

Key words

angiotensin II receptor antagonist - hypertension - anti-hypertension drug - tumor - prostate cancer

Full Text

References

References
1 Laragh J. The Renin System and the Renal Regulation of Blood Pressure. In The Kidney: Physiology and Pathophysiology. 2^nd(ed.). New York: Raven Press; 1992: 1411-1453
2 Wong PC, Barnes TB, Chiu AT et al. Losartan (DuP 753), an orally active nonpeptide angiotensin II receptor antagonist. Cardiouasc Drug Rev 1991; 9: 317- 339
3 Hsi JD, Murray MV, Gill A et al. A highly efficient synthesis of RWJ 47639: a novel orally active angiotensin II receptor antagonist. Bioorg Med Chem Lett 1993; 3: 1523-1526
4 Poss MA. Indole-and benzimidazole-substituted imidazole and benzimidazole derivatives: EP0488532 1992;
5 Poss MA. Indole-and benzimidazole-substituted imidazole and benzimidazole derivatives: US5208235 1993;
6 Poss MA, Atwal KS. Indole and benzimidazole-substituted dihydropyrimidine derivatives: US5212177 1993;
7 Spiegel S, Desai NN, Poss MA.. Antihypertensive indole- and benzimidazole- substituted imidazole and bezimidazole derivatives. US5374615 1994;
8 Dhanoa DS, Bagley SW, Chang RSL et al. Non-Peptide Angiotensin II Receptor Antagonists. 1. Design, Synthesis, and Biological Activity of N-Substituted Indoles and Dihydroindoles. J Med Chem 1993; 36: 4230-4238
9 Khakoo AY, Sidman RL, Pasqualini R et al. Does the rennin-angiotinsin system participate in regulation of human vasculogenesis and angiogenesis? . Cancer Res 2008; 68: 9112-9115
10 Fox SB, Gasparini G, Harris LA et al. Angiogenesis: pathological, prognostic, and growth-factor pathways and their link to trial design and anticancer drugs. Lancet Oncol 2001; 2: 278-279
11 Lallemand JY et al. Etude de derives de indole parresonance magnetique nucleaire. Bull Soc Chim Fr 1970; 4091-4099
12 Da YJ, Yuan WD, Zhu LF et al. Synthesis. anti-hypertensive effect of a novel angiotensin II AT1 receptor antagonist and its anti-tumor activity in prostate cancer. Drug Res 2012; 62: 637
13 Alberto F, Arriba D, Luis A et al. In vitro pharmacological characterization of a new selective angiotensin AT1 receptor antagonist, UR-7280. Eur J Pharmacol 1996; 318: 341-347
14 Scatchard G et al. The attractions of proteins for small molecules and ions. Ann NyAcad Sci 1949; 51: 660-672
15 Nagura J, Yasuda S, Fujishima K et al. Pharmacological profile of ME3221, a novel angiotensin II receptor antagonist. Eur J Pharmacol 1995; 274: 201-211
16 Kaur M, Velmurugan B, Rajamanickam S et al. Gallic acid, an active constituent of grape seed extract, exhibits anti-proliferative, pro-apoptotic and anti-tumorigenic effects against prostate carcinoma xenograft growth in nude mice. Pharmaceutical research 2009; 26: 2133-2140
17 Uemura H, Ishiguro H, Nakaigawa N. Angiotensin II receptor blocker shows antiproliferative activity in prostate cancer cells: a possibility of tyrosine kinase inhibitor of growth factor. Mol Cancer Ther 2003; 2: 1139-1147
18 Polireddy P, Babuji S, Venkateswararao J et al. Evaluation of toxicological and adverse effects produced by losartan. Scholars Research Library 2012; 4: 1027-1037