CGS 34226, a thiol-based dual inhibitor of endothelin converting enzyme-1 and neutral endopeptidase 24.11.
Endothelins (ETs) are potent vasoconstrictors and have been implicated in the pathogenesis of various cardiovascular and renal diseases. In contrast, atrial natriuretic peptide (ANP) is a potent vasorelaxant and diuretic agent, which is mainly degraded by neutral endopeptidase 24.11 (NEP) in vivo. Thus, compounds that can suppress the biosynthesis of ETs by inhibiting endothelin converting enzymes (ECEs), which catalyse the final step of post-translational processing of the vasoconstrictors, while simultaneously potentiating the levels of ANP by inhibiting NEP may have novel therapeutic utility. Through targeted screening of our compound library and subsequent optimization, CGS 34226 was identified as a potent, dual inhibitor of ECE-1 and NEP, inhibiting the enzymes with respective IC(50) values of 11 and 4.6 nM. In vivo, CGS 34226 suppressed the big endothelin-1 (big ET-1)-induced pressor response dose-dependently. At 15 and 90 min after an intravenous dose of 30 mg/kg in anaesthetized rats, this compound inhibited the big ET-1-induced effect by 79% and 65% respectively. In addition, CGS 34226 increased plasma ANP immunoreactivity by 120% up to 4 h after an intravenous dose of 10 mg/kg in conscious rats infused with ANP at a rate of 450 ng/kg per min, intravenously. These results show that CGS 34226 is a potent dual inhibitor of ECE-1 and NEP in vitro and in vivo and that the compound may represent a novel agent for the treatment of cardiovascular and renal dysfunction.
Jeng
Arco Y
AY
Metabolic and Cardiovascular Diseases Research, Novartis Institute for Biomedical Research, 556 Morris Avenue, Summit, NJ 07901, U.S.A. arco.jeng@pharma.novartis.com
Savage
Paula
P
Beil
Michael E
ME
Bruseo
Charles W
CW
Hoyer
Denton
D
Fink
Cynthia A
CA
Trapani
Angelo J
AJ
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D019556:COS Cells; D002462:Cell Membrane / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000302:isolation & purification; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000201:enzymology; D008297:Male; D008666:Metalloendopeptidases; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D010446:Peptide Fragments / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000302:isolation & purification; D011498:Protein Precursors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000302:isolation & purification
C467890:CGS 34226; D019332:Endothelin-1; D016232:Endothelins; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D011498:Protein Precursors; D013438:Sulfhydryl Compounds; D010649:Phenylalanine; D009320:Atrial Natriuretic Factor; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; D000072396:Endothelin-Converting Enzymes