Discovery of highly potent renin inhibitors potentially interacting with the S3' subsite of renin.

To exploit the S3' subsite of renin active site for renin inhibitor design, 42 aliskiren derivatives with modified P2' portion were designed, synthesized and biologically evaluated. Some highly potent renin inhibitors (IC₅₀ < 3 nM) were identified, among which compounds 38 (IC₅₀ = 0.9 nM) and 39 (IC₅₀ = 0.7 nM) were over 2.5-fold more potent than aliskiren (IC₅₀ = 2.3 nM). SAR analysis indicated that incorporation of polar hydrophilic moieties into the P2' portion of renin inhibitors generally enhanced the potency. Consistently with this, molecular modeling study revealed that the triazole part of 39 could provide additional interactions to the S3' subsite of renin active site. Moreover, in vivo evaluation in the double transgenic mouse hypertension model demonstrated that 39 produced greater reduction of the mean arterial blood pressure than ariskiren at the doses of 17.0 and 34.0 μmol/kg, respectively. Taken together, the S3' subsite of renin active site merits further consideration for renin inhibitor design.