Innovation of novel anti-hypertensive drug(s) that inhibit adrenal aldosterone synthase gene (CYP11B2) expression

Abstract

In Japan, hypertensive patients are speculated to be 40 million, and 30 million among them are poor controlled. Moreover, 20% of them are estimated as "resistant hypertension" those are above their target blood pressure even in the simultaneous use of three different classes anti-hypertensive drugs. Recently, aldosterone is recognized as one of the main causes of the etiology of "resistant hypertension." Therefore, it is important to discover novel drugs that inhibit the synthesis and secretion of aldosterone. We recently generated a stable H295R cell line expressing aldosterone synthase gene (CYP11B2) promoter (-1521~+2)/luciferase cDNA chimeric reporter construct. We thereafter established a high-throughput screening (HTS) system for the discovery of novel anti-hypertensive drugs that inhibit angiotensin II-induced CYP11B2 expression using the cell line. After confirmation of its validation (Z' score > 0.5), we performed HTS using Core Library (9,600 chemical compounds) and Validated Compound Library (1,979 chemical compounds) obtained from Drug Discovery Initiative (The University of Tokyo), and Tohoku University Chemical Library (5,562 chemical compounds), respectively. We obtained several hit compounds from each library, and focused on one compound (bortezomib) obtained from Validated Compound Library. The compound did not affect cell viability by WST-1 assay, and was demonstrated to lower blood pressure of Tsukuba Hypertensive Mice, significantly. The compound may therefore be a potential candidate of novel anti-hypertensive drugs in the future.