cgs-35601 and Hypertension

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 concentrations of a number of circulating vasoactive peptidic mediators that are keys to the regulation of the vascular tone. These data suggest that CGS 35601, a triple vasopeptidase inhibitor (VPI), may represent a novel class of antihypertensive drugs and may have the potential to reduce morbidity and mortality from cardiovascular disorders, diabetes and subsequent renal complications. Similar in vivo ACE, NEP, and ECE inhibitory activities were also observed with the orally active prodrug, CGS 37808 (L-tryptophan, N-[[1-[[(2S)-2-(acetylthio)-4-methyl-1-oxopentyl]amino]cyclopentyl]-carbonyl]-, methyl ester.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Aspartic Acid Endopeptidases; Diabetes Mellitus; Endothelin-Converting Enzymes; Enzyme Inhibitors; Heart Failure; Humans; Hypertension; Indoles; Metalloendopeptidases; Neprilysin; Protease Inhibitors

CGS 35601 is a triple vasopeptidase inhibitor (VPI) of angiotensin-converting enzyme, neutral endopeptidase, and endothelin-converting enzyme-1 with respective IC50 values of 22, 2, and 55 nM. We characterized the safety profile and toxicity of escalating doses of CGS 35601 over a 20-day period in chronically instrumented, unrestrained, conscious, male, spontaneously hypertensive rats (SHR). Once instrumented with an arterial catheter, the SHR were placed in metabolic cages allowing daily assessment of hemodynamics and blood sampling for biochemical and hematological measurements. After a 7-day stabilization period, the SHR were divided into 2 groups: Gr. 1, (n = 13 to 18) receiving CGS 35601 at 0.01, 0.1, 1 and 5 mg kg(-1) day(-1) (continuous i.a. infusion) for 5 consecutive days/dose, followed by a 5-day washout; and Gr. 2, (n = 10) receiving vehicle (saline). The highest dose of CGS 35601 dose-dependently reduced MABP from 156 +/- 4 up to 94 +/- 5 mm Hg, whereas heart rate, metabolic, electrolytic, and hematological profiles, growth, diuresis, and renal activity were unaffected, and no hepatic or liver toxicities were observed. These results suggest that this novel triple VPI presents no safety concerns at this stage and may become of interest for the treatment of hypertension and other cardiovascular disorders. Long-term chronic experiments are needed to assess possible angioedema and increases in vascular permeability.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aspartic Acid Endopeptidases; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Endothelin-Converting Enzymes; Heart Rate; Hemodynamics; Hypertension; Indoles; Male; Metalloendopeptidases; Molecular Structure; Neprilysin; Rats; Rats, Inbred SHR

CGS 35601 is a potent triple vasopeptidase inhibitor (VPI) of angiotensin-converting enzyme (ACE), neutral endopeptidase (NEP), and endothelin-converting enzyme (ECE). The aim of the study was to determine the effects of this VPI on the hemodynamic profile of conscious, instrumented, unrestrained spontaneously hypertensive rats (SHR), in comparison to selective inhibitors of ACE and ACE + NEP, than +ECE combined. Circulating plasma concentrations of vasoactive mediators and reactive oxygen species were measured.. Old SHR male were instrumented (arterial catheter) and placed in a metabolic cage for daily hemodynamic measurements and blood samplings. Seven days after surgery, SHR received 1) saline vehicle; 2) increasing doses of the triple CGS 35601 (0.01, 0.1, 1, and 5 mg/kg/d, intra-arterially (i.a.) infusion for 5 d/dose) followed by a 5-day washout period; 3) benazepril (ACE inhibitor), ACE inhibitor + CGS 24592 (NEP inhibitor) and ACE inhibitor + NEP inhibitor + CGS 35066 (ECE inhibitor) (1 or 5 mg/kg/d i.a. infusion for 5 d/combination) followed by a 5-day washout period.. The lowest dose of CGS 35601 had no effect. Doses at 0.1, 1, and 5 mg/kg/d reduced mean arterial blood pressure by 10%, 22%, and 40%, respectively. Heart rate was unaffected in all groups. CGS 35601 decreased concentrations of angiotensin II (Ang II), endothelin-1 (ET-1), and pro-atrial natriuretic peptide (proANP), and increased those of big ET-1, atrial natriuretic peptide (ANP), bradykinin (BK), and hydrogen peroxide (H2O2) dose dependently.. The blood pressure-lowering effect of this triple VPI was superior to that of the other VPI in this preclinical rat model of hypertension. Further experiments are needed to assess triple VPI to other combinations in other models with regard to efficacy and angioedema. Only then it may constitute a first-in-class approach for the treatment of hypertension and other cardiovascular disorders.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Aspartic Acid Endopeptidases; Atrial Natriuretic Factor; Benzazepines; Benzofurans; Blood Pressure; Dose-Response Relationship, Drug; Endothelin-1; Endothelin-Converting Enzymes; Hypertension; Indoles; Male; Metalloendopeptidases; Neprilysin; Nitric Oxide; Organophosphonates; Phenylalanine; Protease Inhibitors; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Rats, Wistar; Reactive Oxygen Species