Dual inhibition of angiotensin converting enzyme and neutral endopeptidase 24.11

Publisher Summary This chapter presents an overview of different approaches leading to the discovery of dual angiotensin converting enzyme and neutral endopeptidase (ACE/NEP) inhibitors. ACE is a membrane bound glycoprotein, which plays a major role in the renin-angiotensin-aldosterone system by cleaving the C-terminal dipeptide portion (His-Leu) of angiotensin I (AI) to produce angiotensin II (AII) which is a potent vasoconstrictor. On the other hand, neutral endopeptidase is a 90 kDa membrane bound glycoprotein, which hydrolyzes peptides at the amino group of hydrophobic residues. Design of novel compounds which inhibits both ACE and NEP has been facilitated by examination of the structural features of the selective ACE and selective NEP inhibitors. ACE and NEP are both zinc metalloproteases with one zinc atom in their active site. The thiol group seems to be a good functional group to incorporate in the design of dual ACE/NEP inhibitors as it binds to zinc ion with high affinity.