CGS 35601 and its Orally Active Prodrug CGS 37808 as Triple Inhibitors of Endothelin-converting Enzyme-1, Neutral Endopeptidase 24.11, and Angiotensin-converting Enzyme
| Autor: | Michael E. Beil, Arco Y. Jeng, Charles W. Bruseo, Angelo J. Trapani, Fariborz Firooznia, Paula Savage |
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| Rok vydání: | 2004 |
| Předmět: |
Male
medicine.medical_specialty Indoles Time Factors Endothelin converting enzyme 1 medicine.medical_treatment Administration Oral Angiotensin-Converting Enzyme Inhibitors Blood Pressure CHO Cells Endothelin-Converting Enzymes Peptidyl-Dipeptidase A Pharmacology Transfection Rats Sprague-Dawley Cricetulus Atrial natriuretic peptide Cricetinae Internal medicine Renin–angiotensin system medicine Animals Aspartic Acid Endopeptidases Humans Prodrugs Protease Inhibitors education Neprilysin education.field_of_study Endothelin-1 biology Chemistry Angiotensin II Metalloendopeptidases Angiotensin-converting enzyme Dipeptides Prodrug Rats Endocrinology Injections Intravenous biology.protein Rabbits Diuretic Cardiology and Cardiovascular Medicine Atrial Natriuretic Factor |
| Zdroj: | Journal of Cardiovascular Pharmacology. 44:S211-S215 |
| ISSN: | 0160-2446 |
| Popis: | CGS 35601 is a potent triple inhibitor of endothelinconverting enzyme-1, neutral endopeptidase 24.11, and angiotensinconverting enzyme. It inhibited the activities of these three enzymes with IC50 values of 55, 2 and 22 nM, respectively. In conscious rats, CGS 35601 suppressed the big endothelin-1-induced pressor response by 82% and 72% at 30 and 120 minutes, respectively, following injection at a dose of 10 mg/kg, intravenously. At the same dose, CGS 35601 increased plasma atrial natriuretic peptide (ANP) immunoreactivity by 170% for up to 4 hours in conscious rats infused with ANP, and it inhibited the angiotensin I-induced pressor response by 74-94% within the first 2 hours after dosing. Similar in vivo activities were also observed with its orally active prodrug, CGS 37808. This compound blocked the big endothelin-1- induced pressor response by 71% and 67% at 30 and 120 minutes, respectively, after an oral dose of 10 mgEq/kg in conscious rats. It also increased plasma ANP immunoreactivity by 103% for up to 4 hours and inhibited the angiotensin I-induced pressor response by an average of 49% within the first 4 hours after the same dosing regimen. By suppressing the biosyntheses of endothelin-1 and angiotensin II, two potent vasoconstrictors, while simultaneously potentiating the circulating levels of ANP, a vasorelaxant and diuretic, CGS 35601 and CGS 37808 may represent novel agents for the treatment of cardiovascular and renal diseases. |
| Databáze: | OpenAIRE |
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