Small-molecule inhibitor: aliskiren

Name

History: The discovery of aliskiren can be traced back to efforts to develop stable analogues of the bond in angiotensinogen that is cleaved by renin. The discovery of aliskiren has been described by Wood et al. (2003).
Peptidases inhibited: Renin. K_i 0.6 nM for human renin. Shows negligible inhibition of pepsin, cathepsin D), cathepsin E and HIV-1 retropepsin (Wood et al., 2003). Inhibition of renin from other species is weaker, sometimes by several orders of magnitude.
Mechanism: Inhibition is reversible. The mode of binding to the active site of renin has been demonstrated crystallographically (Wood et al., 2003).
Pharmaceutical relevance: Hypertension is a major risk factor for cardiovascular diseases, and control of hypertension is a proven therapeutic strategy. The hypertensive peptide, angiotensin II, is released from angiotensinogen by two proteolytic steps, the first of which is catalysed by the aspartic endopeptidase renin. Renin inhibitors have clear therapeutic potential, but early compounds generally had poor pharmacokinetic properties. Aliskiren is one of a new class of compounds that have the potential for treatment of hypertension.
DrugBank: DB01258

CID at PubChem: 5493444
ChEBI: 601027
Structure
Chemical/biochemical name: 2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy- 2,7-diisopropyl-8-[4-methoxy-3- (3-methoxypropoxy-)phenyl]-octanamide).
Formula weight: 552

Comment: Aliskiren is a dipeptide-like, hydroxyethylene transition state mimetic.
Reviews: Wood et al. (2003)