Discovery of a novel renin inhibitor SPH3127

Abstract

Renin is the rate-limiting and first step of the renin-angiotensin system, and direct renin inhibitors (DRIs) show potent hypotensive effect without increasing plasma renin activity, unlike ARBs and ACE inhibitors. Furthermore, clinical studies have demonstrated the potential of DRIs for renal and cardiac protection. Although DRIs have been searched for several decades, most of them have poor pharmacokinetics and oral absorption because of peptide-like structures or nonpeptide-like structures with molecular weight close to 700. Aliskiren, which was approved as the first orally bioavailable DRI in 2007, also has low bioavailability (2~3%). We discovered SPH3127, which has a nonpeptide-like structure and molecular weight less than 500. It has higher bioavailability and more potent hypotensive effect in non-clinical models than Aliskiren, and is currently under Phase II clinical trial. In this report, we show the details of optimization to improve renin inhibitory activity and pharmacokinetics without significant increase in molecular weight.