Discovery Of Potent And Low-toxicity Angiotensin Ⅱ Receptor Type 1（AT₁） Blockers: Design, Synthesis And Biological Evaluation Of 6-substituted Aminocarbonyl Benzimidazoles With A Chiral Center

Hypertension is a lifelong condition, and patients with high blood pressure need to take medicine daily. With the development of the global society, hypertension challenges not only the people in Western countries but also the population worldwide. For instance, the hypertensive morbidity rate of Chinese adults may reach 30%, as predicted by the Centers for Disease Control of China. Hence, the effectiveness and safety of antihypertensive drugs, which underwent several years as follows: diuretics in 1960 s, β-blockers in 1970 s, angiotensin converting enzyme inhibitors and calcium channel antagonists in 1980 s, angiotensin II receptor blockers(ARBs) in 1990 s, and renin inhibitors recently, should urgently be promoted. Furthermore, the discovery of better and safer ARBs is a meaningful work because sartans are still the first-line therapy for clinical hypertension.Research efforts of our group in the last decade have focused on finding antihypertensive compounds with significant effect and low toxicity. Considering our understanding of benzimidazole derivatives in the field of medicinal chemistry, we were curious about the effect of this kind of structure, which showed good activity at positions 5–7. Among these reports, a carboxylic acid function and its derivatives at the position 5 or 7 were favorable for Ang II antagonism. In our previous report, the derivatives of 6-aminocarbonyl and 6-acylamino benzimidazoles were developed and evaluated with favorable antagonistic activity with in vitro and in vivo studies. Specifically, 4’-((4-methyl-6-(phenethylcarbamoyl)-2-n-propyl-1H-benzimidazol-1-yl)methyl)-[1,1’-biphenyl]-2-carboxylic acid(Phenasartan), which recently passed the acute toxicity(LD50 = 12 g/kg), genotoxicity(negative), and long-term(chronic) toxicity tests, showed extremely ideal results for toxicology studies. Moreover, the application and preparation of chiral drugs represent one of the orientations of medicine development in the industry, but ARBs with asymmetric center have been rarely reported.Thus, in this report, I envisaged that the insertion of a chiral substituent group can improve the specificity of antihypertensive efficacy of the parent structure Phenasartan. Encouraged by the success of Candesartan and Fimasartan, oxygen or sulfur atom was also introduced at the position 2 or 6 of benzimidazole for the same expectation. In the beginning, three new ethyl2-thioalkyl-4-methyl-1H-benzimidazole-6-carboxylates and one new ethyl 2-alkoxy-4-methyl-1H-benzimidazole-6-carboxylate were synthesized. Underwent condensation,alkylation,deprotection sequence without any loss of optical activity, 40 novel angiotensin II receptor type 1(AT1) receptor blockers bearing 6-substituted carbamoyl benzimidazoles with a chiral center were synthesized as the first step to develop new antihypertensive agents and understand their pharmacodynamic and pharmacokinetic properties. The newly synthesized compounds were tested for their potential ability to displace [125I] Sar1 Ile8-Ang II, which was specifically bound to human AT1 receptor. Radioligand binding assays revealed nanomolar affinity in several compounds under study. The IC50 values of nine ligands, 1S(IC50 = 19.5 n M), 8S(IC50 = 5.0 n M), 8R(IC50 = 1.1 n M), 13R(IC50 = 7.3 n M), 14S(IC50 = 6.3 n M), 14R(IC50 = 3.5 n M), 20S(IC50 = 2.7 n M), and 20R(IC50 = 1.4 n M), were higher than those of Losartan(IC50 = 28 n M). The screening of decreased blood pressure in spontaneous hypertensive rats displayed that compound 8S was equipotent with Losartan, whereas compounds 13 R, 14 R, and 14 S were slightly ahead of Losartan, and the most significant activity was demonstrated by compound 8R, which reduced the MBP to 45 mm Hg. Compound 8R was further observed via pharmacokinetic, toxicology, and chronic administration studies. The long-acting and low-toxicity(LD50=3.6g/kg) characteristics of compound 8R proved that it should be an attractive candidate for the treatment of high blood pressure. Moreover, the molecular docking work showed that compound 8R can interact with AT1 receptor through forceful and multiple affinities pointed to different pockets and active sites. In particular, this configuration R of the inserted hydrophobic group with the optimal activity was explained on the virtual model based on the results of biological evaluations.