Abstract
A series of 13- and 14-membered ring lactam derivatives 9a,b, 10, 11, and 12a-c was prepared from L-cysteine. Compounds 9a,b and 12a,b were tested in vitro for inhibition of neutral endopeptidase 24.11 (NEP) and angiotensin converting enzyme (ACE) inhibition. The structure-activity profile of the series is discussed. Compound 9b, a 13-membered ring macrocyclic lactam, had an NEP IC50 of 18 nM and an ACEIC50 of 12 nM in vitro and showed dual plasma inhibition after intravenous or oral administration.
MeSH terms
-
Angiotensin-Converting Enzyme Inhibitors / chemical synthesis*
-
Angiotensin-Converting Enzyme Inhibitors / pharmacokinetics
-
Angiotensin-Converting Enzyme Inhibitors / pharmacology
-
Animals
-
Antihypertensive Agents / chemical synthesis*
-
Antihypertensive Agents / pharmacology
-
Cysteine / analogs & derivatives*
-
Cysteine / chemical synthesis
-
Cysteine / pharmacokinetics
-
Cysteine / pharmacology
-
Hypertension / chemically induced
-
Hypertension / enzymology
-
Kinetics
-
Magnetic Resonance Spectroscopy
-
Molecular Structure
-
Neprilysin / antagonists & inhibitors*
-
Neprilysin / blood
-
Peptides, Cyclic / chemical synthesis*
-
Peptides, Cyclic / pharmacokinetics
-
Peptides, Cyclic / pharmacology
-
Rats
-
Rats, Sprague-Dawley
-
Stereoisomerism
-
Structure-Activity Relationship
Substances
-
Angiotensin-Converting Enzyme Inhibitors
-
Antihypertensive Agents
-
Peptides, Cyclic
-
6-(mercaptomethyl)-5-oxo-1-thia-4-azacyclotridecane-3-carboxylic acid
-
Neprilysin
-
Cysteine