The First Preclinical Pharmacotoxicological Safety Assessment of CGS 35601, a Triple Vasopeptidase Inhibitor, in Chronically Instrumented, Conscious, and Unrestrained Spontaneously Hypertensive Rats

Daull, Philippe; Lepage, Raymond; Benrezzak, Ouhida; Cayer, Julie; Beaudoin, Myriam; Belleville, Karine; Blouin, A; Sirois, Pierré; Nantel, F.; Jeng, Arco Y.; Battistini, Bruno

doi:10.1080/01480540600566717

Cited by 8 publications

(6 citation statements)

References 28 publications

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“…The system may be amenable to therapeutic intervention. For example, neutral endopeptidase inhibitors are in clinical development for the treatment of arterial hypertension and heart failure (40). Neutral endopeptidase inhibition may promote lipid mobilization and oxidation.…”

Section: Discussionmentioning

confidence: 99%

Atrial Natriuretic Peptide Induces Postprandial Lipid Oxidation in Humans

et al. 2008

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OBJECTIVE-Atrial natriuretic peptide (ANP) regulates arterial blood pressure. In addition, ANP has recently been shown to promote human adipose tissue lipolysis through cGMPmediated hormone-sensitive lipase activation. We hypothesized that ANP increases postprandial free fatty acid (FFA) availability and energy expenditure while decreasing arterial blood pressure. RESEARCH DESIGN AND METHODS-We infused human ANP (25 ng ⅐ kgϪ1 ⅐ min Ϫ1 ) in 12 men (age 32 Ϯ 0.8 years, BMI 23.3 Ϯ 0.4 kg/m 2 ) before, during, and 2 h after ingestion of a standardized high-fat test meal in a randomized, double-blind, cross-over fashion. Cardiovascular changes were monitored by continuous electrocardiogram and beat-by-beat blood pressure recordings. Metabolism was monitored through venous blood sampling, intramuscular and subcutaneous abdominal adipose tissue microdialysis, and indirect calorimetry.RESULTS-ANP infusion decreased mean arterial blood pressure by 4 mmHg during the postprandial phase (P Ͻ 0.01 vs. placebo). At the same time, ANP induced lipolysis systemically (P Ͻ 0.05 vs. placebo) and locally in subcutaneous abdominal adipose tissue (P Ͻ 0.0001 vs. placebo), leading to a 50% increase in venous glycerol (P Ͻ 0.01) and FFA (P Ͻ 0.05) concentrations compared with placebo. The increase in FFA availability with ANP was paralleled by a 15% increase in lipid oxidation rates (P Ͻ 0.05 vs. placebo), driving a substantial increase in postprandial energy expenditure (P Ͻ 0.05 vs. placebo). A modest mismatch between energy intake and expenditure elicits major changes in body weight over years. Total daily energy expenditure comprises resting metabolic rate, physical activity, and postprandial thermogenesis. Measures that increase postprandial thermogenesis could prevent or treat obesity. Pharmacological strategies to augment energy expenditure have been unsuccessful because of side effects (1). Manipulation of adrenergic transmission is associated with increased thermogenesis, blood pressure elevations, and other cardiac side effects (2). Atrial natriuretic peptide (ANP) has recently been shown to promote adipose tissue lipolysis through cGMP-mediated, hormone-sensitive lipase activation (3). ANP-mediated lipolysis has only been observed in primates such as macaques and humans but not in other species (4). ANP increases circulating free fatty acid (FFA) levels in human subjects (5-8). Previous studies with adrenergic agonists suggested that increased circulating FFA concentrations can drive an increase in energy expenditure (9). In our earlier studies, ANP-mediated lipolysis did not alter energy expenditure in the fasted state, whereas lipid oxidation rate increased slightly (6,8). We now tested the hypothesis that ANP augments postprandial FFA availability, lipid oxidation, and energy expenditure while concomitantly decreasing blood pressure in healthy young men. CONCLUSIONS-Our RESEARCH DESIGN AND METHODSWe recruited 12 healthy, nonoverweight, nonobese individuals aged 32 Ϯ 0.8 years with BMI 23.3 Ϯ 0.4 kg/m 2 . Subjects did not ...

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Section: Discussionmentioning

confidence: 99%

Atrial Natriuretic Peptide Induces Postprandial Lipid Oxidation in Humans

et al. 2008

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“…Even at the highest dose for 5 days, a treatment condition that caused a decrease in MABP to values below those of the normotensive counterparts, CGS 35601 had no untoward effects on hepatic or renal functions, as measured by several biomarkers in the blood and urine. Furthermore, hematological profile, electrolyte and acid-base balance, as well as carbohydrate or lipid metabolisms were not altered by CGS 35601 (15).…”

Section: Safety Pharmacological Profilementioning

confidence: 87%

“…Acute short-term treatment with increasing doses of CGS 35601 (0.01, 0.1, 1, and 5 mg/kg/day for 5 days/dose, i.a., or 0.1, 1, and 5 mg/kg/day for 6 days/dose, i.a.) in chronically instrumented and conscious rats (SHR, Sprague-Dawley, DSS or ZDF-fatty rats) presented no significant toxicity (12)(13)(14)(15). Even at the highest dose for 5 days, a treatment condition that caused a decrease in MABP to values below those of the normotensive counterparts, CGS 35601 had no untoward effects on hepatic or renal functions, as measured by several biomarkers in the blood and urine.…”

Section: Safety Pharmacological Profilementioning

confidence: 99%

CGS 35601, a Triple Inhibitor of Angiotensin Converting Enzyme, Neutral Endopeptidase and Endothelin Converting Enzyme

Battistini

Daull

Jeng³

2006

Cardiovascular Drug Reviews

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CGS 35601 (L-tryptophan, N-[[1-[[(2S)-2-mercapto-4-methyl-1-oxopentyl]amino]-cyclopentyl]carbonyl]) is one of a few single molecules capable of inhibiting the activities of angiotensin-converting enzyme (ACE), neutral endopeptidase (NEP) and endothelin converting enzyme (ECE) simultaneously, with IC 50 values of 22, 2, and 55 nM, respectively. Through the inhibition of ACE and ECE, it blocks the conversion of angiotensin I (AI) and big endothelin-1 (big ET-1) into the two most potent peptidic vasoconstrictors, angiotensin II (AII) and ET-1, respectively. By inhibiting NEP, CGS 35601 also prevents the degradation of peptidic vasodilators such as bradykinin (BK), natriuretic peptides (NPs) and adrenomedullin (ADM) and, hence, modulates the secondary release of other vasoactive mediators such as nitric oxide (NO) and prostaglandins.In chronic (30 days) experiments, CGS 35601 is well tolerated with a very good safety profile in healthy normotensive, hypertensive and type 2 diabetic rats. The antihypertensive efficacy of CGS 35601 was demonstrated in chronically instrumented, unrestrained and conscious rat models of hypertension (SHR and DSS) and type 2 diabetes (ZDF-fatty). It lowered blood pressure effectively as well as modulated plasma concentra-

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“…CGS 35601, a triple vasopeptidase inhibitor, prevents the activities of ACE, NEP and ECE‐1 (Trapani et al ., ) and significantly reduced both systolic and diastolic blood pressure in a number of preclinical rodent models of hypertension (Daull et al ., 2005; 2006a). Further, a preclinical safety profile assessment of CGS 35601 showed it to have no effect on either hepatic or liver toxicities (Daull et al ., ). Although these triple inhibitors may represent the future of peptidase inhibitors for the treatment of disease (Table ), no clinical trials using triple peptidase inhibitors have yet been conducted.…”

Section: Cell‐surface Peptidases Regulate the Availability Of Gpcr LImentioning

confidence: 97%

Roles of proteolysis in regulation of GPCR function

Cottrell

2013

British J Pharmacology

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The enzymatic activity of peptidases must be tightly regulated to prevent uncontrolled hydrolysis of peptide bonds, which could have devastating effects on biological systems. Peptidases are often generated as inactive propeptidases, secreted with endogenous inhibitors, or they are compartmentalized. Propeptidases become active after proteolytic removal of N‐terminal activation peptides by other peptidases. Some peptidases only become active towards substrates only at certain pHs, thus confining activity to specific compartments or conditions. This review discusses the different roles proteolysis plays in regulating GPCRs. At the cell‐surface, certain GPCRs are regulated by the hydrolytic inactivation of bioactive peptides by membrane‐anchored peptidases, which prevent signalling. Conversely, cell‐surface peptidases can also generate bioactive peptides, which directly activate GPCRs. Alternatively, cell‐surface peptidases activated by GPCRs, can generate bioactive peptides to cause transactivation of receptor tyrosine kinases, thereby promoting signalling. Certain peptidases can signal directly to cells, by cleaving GPCR to initiate intracellular signalling cascades. Intracellular peptidases also regulate GPCRs; lysosomal peptidases destroy GPCRs in lysosomes to permanently terminate signalling and mediate down‐regulation; endosomal peptidases cleave internalized peptide agonists to regulate GPCR recycling, resensitization and signalling; and soluble intracellular peptidases also participate in GPCR function by regulating the ubiquitination state of GPCRs, thereby altering GPCR signalling and fate. Although the use of peptidase inhibitors has already brought success in the treatment of diseases such as hypertension, the discovery of new regulatory mechanisms involving proteolysis that control GPCRs may provide additional targets to modulate dysregulated GPCR signalling in disease.

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The First Preclinical Pharmacotoxicological Safety Assessment of CGS 35601, a Triple Vasopeptidase Inhibitor, in Chronically Instrumented, Conscious, and Unrestrained Spontaneously Hypertensive Rats

Cited by 8 publications

References 28 publications

Atrial Natriuretic Peptide Induces Postprandial Lipid Oxidation in Humans

Atrial Natriuretic Peptide Induces Postprandial Lipid Oxidation in Humans

CGS 35601, a Triple Inhibitor of Angiotensin Converting Enzyme, Neutral Endopeptidase and Endothelin Converting Enzyme

Roles of proteolysis in regulation of GPCR function

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