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

Abstract

CGS 35601 is a potent triple inhibitor of endothelin-converting enzyme-1, neutral endopeptidase 24.11, and angiotensin-converting 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.

Pharmacokinetics and Pharmacodynamics of LCZ696, a Novel Dual‐Acting Angiotensin Receptor—Neprilysin Inhibitor (ARNi)

“…The dTGR (n = 6 per treatment group) were surgically implanted with an aortic catheter and radio transmitter (Data Sciences, Inc, Laurel, Maryland) for measurement of mean arterial pressure. The NEP‐inhibitory effect of LCZ696 was determined in chronically cannulated Sprague‐Dawley rats (n = 4 per treatment group) infused (450 ng/kg/min) with exogenous ANP (1–28) (American Peptide Company, Sunnyvale, California) 14 . Potentiation of plasma ANP immunoreactivity (ANPir) levels was used as an index of NEP inhibition in vivo.…”

The endothelin system as a therapeutic target in cardiovascular disease: great expectations or bleak house?

“…Thus, blockade of ET‐1 synthesis and NEP concurrently may unmask these sought after benefits and provide agents with improved clinical efficacy. Triple ACE/ECE/NEP inhibitors have been pursued more recently with the proposition that, since patients with heart failure and hypertension benefit from ACE inhibition, a single compound (such as CGS 35601; Trapani et al , 2004 ) that blocked ACE, ECE and NEP might provide benefits in cost and compliance. It seems unlikely, however, that at any given dose, a single molecule will possess optimal inhibition kinetics for three distinct enzyme systems.…”

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

“…CGS 35601 inhibited ACE, NEP and ECE-1 activities with IC 50 values of 55, 2, and 22 nM, respectively (47).…”

“…By intravenous administration CGS 35601, 10 mg/kg, produced a sustained (for at least 4 h) increase in the plasma ANP concentration of 170%, as compared to the vehicle control (47 Inhibition of ECE-1 activity by CGS 35061 in vivo was evaluated by the big ET-1-induced pressor response in conscious rats. It has been shown that i.v.…”