Pharmacological profile of a non-peptidic dual inhibitor of neutral endopeptidase 24.11 and endothelin-converting enzyme.
CGS 26303 is a potent and structurally unique non-peptidic inhibitor of neutral endopeptidase (NEP) capable of protecting atrial natriuretic peptide (ANP) from enzymatic degradation. In addition, CGS 26303 displays modest endothelin-converting enzyme (ECE) inhibitory activity in vitro. Unlike CGS 24592, a potent but selective NEP inhibitor, CGS 26303 significantly blocks endothelin-1 production in rats after exogenous administration of big ET-1 and reduces the mean arterial pressure in spontaneously hypertensive rats during chronic administration. These results suggest that CGS 26303 represents a new class of therapeutic agents with potential benefits for the treatment of cardiovascular and renal disorders.
De Lombaert
S
S
Research Department, CIBA-GEIGY Corporation, Summit, New Jersey 07901.
Ghai
R D
RD
Jeng
A Y
AY
Trapani
A J
AJ
Webb
R L
RL
D000595:Amino Acid Sequence; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D009320:Atrial Natriuretic Factor / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects*; D002462:Cell Membrane / Q000378:metabolism; D019332:Endothelin-1; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000096:biosynthesis / Q000494:pharmacology; D007672:Kidney Cortex / Q000201:enzymology; D007700:Kinetics; D008297:Male; D008666:Metalloendopeptidases; D008969:Molecular Sequence Data; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D009842:Oligopeptides; D063065:Organophosphonates / Q000494:pharmacology*; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D011498:Protein Precursors / Q000096:biosynthesis; D051381:Rats; D011918:Rats, Inbred SHR; D013379:Substrate Specificity; D013777:Tetrazoles / Q000494:pharmacology*
C086164:CGS 24592; D019332:Endothelin-1; D016232:Endothelins; D009842:Oligopeptides; D063065:Organophosphonates; D011498:Protein Precursors; D013777:Tetrazoles; C089987:CGS 26303; D010649:Phenylalanine; D009320:Atrial Natriuretic Factor; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; D000072396:Endothelin-Converting Enzymes