Recent progress on the discovery of non-peptidic direct renin inhibitors as antihypertensives

Introduction: The renin-angiotensin-aldosterone system (RAAS) has long been established as being a key cascade or pathway in the regulation of blood pressure and homeostasis of body fluid volume. The aspartic protease renin is responsible for the initial and rate-limiting step of the RAAS, thus inhibition of renin would favor more complete blockade of the RAAS. Therefore, direct renin inhibitors (DRIs) have been considered to be attractive agents for the treatment of hypertension. However, from the medicinal chemistry point of view, the identification of orally bioavailable, efficacious and safe low molecular weight DRIs has proven very challenging. To date, Aliskiren (Tekturna®, Rasilez®; Novartis) is the only DRI that has reached the market (FDA approved in 2007) for the treatment of hypertension. Areas covered: The present review summarizes the recent scientific accounts describing the design of new non-peptidic DRIs published from 2009-2012. Chemical structures, and preclinical DMPK properties and safety profile are collected from public scientific literatures and patent filings identified in both the Thomson Pharma and SciFinder databases. The results of early clinical trials of new candidate DRIs are also discussed. Expert opinion: The vast medicinal chemistry efforts on structure-based design of non-peptidic DRIs since the last decade have identified new chemical spaces for tight binding to renin and for gaining proper balance of physicochemical properties, potency, efficacy, and safety. However, the criteria for the selection of development candidates have become increasingly demanding, because new antihypertensives are expected to demonstrate a clear differentiation in their clinical profile, in addition to blood pressure lowering and to the benefit of the patients, as compared to established drug treatment paradigms. Hence, developing a new generation of DRIs remains a formidable task