Chemical Synthesis, Safety and Efficacy of Antihypertensive Candidate Drug 221s (2,9)

Hypertension is the main risk factor of cardiovascular and cerebrovascular diseases. In this paper, a novel compound known as 221s (2,9), which includes tanshinol, borneol and a mother nucleus of ACEI, was synthesized by condensation esterification, deprotection, amidation, deprotection, and amidation, with borneol as the initial raw material, using the strategy of combinatorial molecular chemistry. The structure of the compound was confirmed by H-1 NMR, C-13 NMR, and high-resolution mass spectrometry, with a purity of more than 99.5%. The compound 221s (2,9) can significantly reduce the systolic and diastolic blood pressure of SHR rats by about 50 mmHg and 35 mmHg after 4 weeks of administration. The antihypertensive effect of 221s (2,9) is equivalent to that of captopril. The use of 221s (2,9) can reduce the content of Ren, Ang II and ACE in the serum of SHR rats, inhibit the RAAS and enhance the vascular endothelial function by upregulating the level of NO. Pathological studies in this area have shown that high dosage of 221s (2,9) can notably protect myocardial fibrosis in rats and reduce the degeneration and necrosis of myocardial fibers, inflammatory cell infiltration, and proliferation of fibrous tissue in the heart of rat. Therefore, the existing work provided a foundation for preclinical research and follow-up clinical research of 221s (2,9) as a new drug.

Automated summary

In this study, a novel compound 221s (2,9) was synthesized using the strategy of combinatorial molecular chemistry, which showed significant antihypertensive effects in SHR rats and had similar efficacy to captopril. The compound also reduced the levels of Ren, Ang II, and ACE in the serum, inhibited RAAS, and enhanced vascular endothelial function. Pathological studies demonstrated its protective effects on myocardial fibrosis and reduction of cardiac degeneration, necrosis, inflammatory cell infiltration, and fibrous tissue proliferation. These findings provide a foundation for further preclinical and clinical research of 221s (2,9) as a new drug.