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 IC50 values of 11 and 4.6nM. In vivo, CGS 34226 suppressed the big endothelin-1 (big ET-1)-induced pressor response dose-dependently. At 15 and 90min after an intravenous dose of 30mg/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 4h after an intravenous dose of 10mg/kg in conscious rats infused with ANP at a rate of 450ng/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.
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September 2002
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Conference Article|
September 01 2002
CGS 34226, a thiol-based dual inhibitor of endothelin converting enzyme-1 and neutral endopeptidase 24.11
Y. Arco JENG;
1Metabolic and Cardiovascular Diseases Research, Novartis Institute for Biomedical Research, 556 Morris Avenue, Summit, NJ 07901, U.S.A.
Dr A. Y. Jeng, Bldg. 130, Room 2227, Novartis Pharmaceuticals Corporation, 556 Morris Avenue, Summit, NJ 07901, U.S.A. (e-mail [email protected]).
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Paula SAVAGE;
Paula SAVAGE
1Metabolic and Cardiovascular Diseases Research, Novartis Institute for Biomedical Research, 556 Morris Avenue, Summit, NJ 07901, U.S.A.
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Michael E. BEIL;
Michael E. BEIL
1Metabolic and Cardiovascular Diseases Research, Novartis Institute for Biomedical Research, 556 Morris Avenue, Summit, NJ 07901, U.S.A.
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Charles W. BRUSEO;
Charles W. BRUSEO
1Metabolic and Cardiovascular Diseases Research, Novartis Institute for Biomedical Research, 556 Morris Avenue, Summit, NJ 07901, U.S.A.
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Denton HOYER;
Denton HOYER
1Metabolic and Cardiovascular Diseases Research, Novartis Institute for Biomedical Research, 556 Morris Avenue, Summit, NJ 07901, U.S.A.
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Cynthia A. FINK;
Cynthia A. FINK
1Metabolic and Cardiovascular Diseases Research, Novartis Institute for Biomedical Research, 556 Morris Avenue, Summit, NJ 07901, U.S.A.
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Angelo J. TRAPANI
Angelo J. TRAPANI
1Metabolic and Cardiovascular Diseases Research, Novartis Institute for Biomedical Research, 556 Morris Avenue, Summit, NJ 07901, U.S.A.
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Publisher: Portland Press Ltd
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2002 The Biochemical Society and the Medical Research Society
2002
Clin Sci (Lond) (2002) 103 (s2002): 98S–101S.
Citation
Y. Arco JENG, Paula SAVAGE, Michael E. BEIL, Charles W. BRUSEO, Denton HOYER, Cynthia A. FINK, Angelo J. TRAPANI; CGS 34226, a thiol-based dual inhibitor of endothelin converting enzyme-1 and neutral endopeptidase 24.11. Clin Sci (Lond) 1 September 2002; 103 (s2002): 98S–101S. doi: https://doi.org/10.1042/CS103S098S
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