The P1N-isopropyl motif bearing hydroxyethylene dipeptide isostere analogues of aliskiren are in vitro potent inhibitors of the human aspartyl protease renin

Novel nonpeptide small molecule renin inhibitors bearing an N-isopropyl P1 motif were designed based on initial lead structures 1 and aliskiren (2). (P3–P1)-Benzamide derivatives such as 9a and 34, as well as the corresponding P1 basic tertiary amine derivatives 10 and 35 were found to display low nanomolar inhibition against human renin in vitro.

Graphical abstractNew (P1–P3) modified analogues of aliskiren (2), a first-in-class orally efficacious direct renin inhibitor for the treatment of hypertension, are disclosed as in vitro low nanomolar inhibitors. Compound 9a lowered mean arterial blood pressure significantly in sodium-depleted marmosets when administered at 3 mg/kg orally.Figure optionsDownload full-size imageDownload as PowerPoint slide