Dual metalloprotease inhibitors.v. Utilization of bicyclic azepinonethiazolidines and azepinonetetrahydrothiazines in constrained peptidomimetics of mercaptoacyl dipeptides

doi:10.1016/0960-894X(95)00109-7

Bioorganic & Medicinal Chemistry Letters

Volume 5, Issue 7, 6 April 1995, Pages 753-758

https://doi.org/10.1016/0960-894X(95)00109-7 Get rights and content

Abstract

Incorporation of mercaptoacetyl or mercaptopropanoyl groups into azepinonethiazolidine and azepinonetetrahydrothiazine carboxylic acids provided conformationally restricted peptidomimetics of Ala-Pro exhibiting potent dual activity in vitro versus ACE and NEP.

A series of conformationally constrained dipeptide mimetics of Ala-Pro yielded potent dual-acting inhibitors of both angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP).

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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.
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Dual metalloprotease inhibitors.v. Utilization of bicyclic azepinonethiazolidines and azepinonetetrahydrothiazines in constrained peptidomimetics of mercaptoacyl dipeptides

Abstract

J. Biol. Chem.

J. Life Sci.

Kidney Internat.

Life Sci

Bioorg. Med. Chem. Letters

Bioorg. Med. Chem. Letters

Bioorg. Med. Chem. Letters

Bioorg. Med. Chem. Letters

Bioorg. Med. Chem. Letters

Trends Pharmacol. Sci.

C. R. Soc. Biol.

Biochem. Soc. Trans.

J. Med Chem.

J. Med. Chem.

J. Med. Chem.