Abstract
We have previously reported the design of a lead compound 1a for the joint inhibition of neprilysin (NEP, EC 3.4.24.11), angiotensin converting enzyme (ACE, EC 3.4.15.1) and endothelin converting enzyme (ECE-1, EC 3.4.24.71), three metallopeptidases which are implicated in the regulation of fluid homeostasis and vascular tone. We report here the synthesis and biological activities of analogues derived from this lead with inhibitory potencies in the nanomolar range for the three enzymes. Compounds 8b and 15c are the most potent triple inhibitors described to date.
MeSH terms
-
Amino Acids / chemistry*
-
Amino Acids / pharmacology*
-
Angiotensin-Converting Enzyme Inhibitors / chemical synthesis*
-
Angiotensin-Converting Enzyme Inhibitors / pharmacology
-
Animals
-
Aspartic Acid Endopeptidases / antagonists & inhibitors
-
Endothelin-Converting Enzymes
-
Indans / chemistry*
-
Indans / pharmacology*
-
Injections, Intravenous
-
Metalloendopeptidases / antagonists & inhibitors*
-
Neprilysin / antagonists & inhibitors
-
Nuclear Magnetic Resonance, Biomolecular
-
Protease Inhibitors / chemistry*
-
Protease Inhibitors / pharmacology*
-
Rats
-
Stereoisomerism
-
Structure-Activity Relationship
-
Sulfhydryl Compounds / chemistry
-
Sulfhydryl Compounds / pharmacology
-
Time Factors
Substances
-
Amino Acids
-
Angiotensin-Converting Enzyme Inhibitors
-
Indans
-
Protease Inhibitors
-
Sulfhydryl Compounds
-
Aspartic Acid Endopeptidases
-
Metalloendopeptidases
-
Neprilysin
-
Endothelin-Converting Enzymes