Recent advances in the discovery of non-peptidic direct renin inhibitors as antihypertensives: new patent applications in years 2000 – 2008

Abstract

Background: The renin-angiotensin-aldosterone system (RAAS) is essential for the regulation of blood pressure and may play a critical role in the pathogenesis of cardiovascular diseases. A strong rationale suggests a more efficient control of RAAS by direct rather than downstream blockade of renin, an angiotensinogen-specific aspartic protease acting at the first, rate-limiting step of the pathway. Vast research efforts since the late 1970s have aimed at developing clinically useful renin inhibitors for the treatment of hypertension and associated co-morbidities. In 2007, aliskiren (Tekturna^®, Rasilez^®; Novartis) was launched as the first orally efficacious direct renin inhibitor. The evolution of non-peptide renin inhibitors interacting with non-substrate recognition sites of the enzyme, such as aliskiren and the 4-aryl-piperidines, during the 1990s encouraged an increasing number of pharmaceutical companies to resume, or newly embark on, drug discovery programs. Objective: This review summarizes the various structural design concepts and the apparent focus of activities presently employed to develop follow-up generations of oral renin inhibitors. Methods: Information was collected from patents, scientific literatures and public sources disclosed during the years 2000 – 2008. Results/conclusion: The structural diversity of small-molecule inhibitors has further increased, including novel basic surrogate transition-state mimetic motifs. Several inhibitors emerged as (pre)clinical candidates, the most advanced having entered Phase II clinical trials.

Keywords::

• aliskiren
• antihypertensive
• aspartic protease
• flap region
• piperidine
• RAAS
• renin-angiotensin-aldosterone system
• renin inhibitor