Towards Triple Vasopeptidase Inhibitors for the Treatment of Cardiovascular Diseases

Cardiovascular diseases (CDs) are among the most encountered pathologies in western countries; with obesity reaching pandemic proportions, they are soon to become a worldwide problem. High blood pressure is the main risk factor for CDs, and its tight control is an imperative for the treatment of complications such as renal diseases, heart failure, and atherosclerosis. Blood homeostasis and vascular tone are regulated through at least 3 major closely interrelated pathways in which zinc metallopeptidases modulate the concentration of vasoactive mediators. Those extensively studied vasopeptidases were therefore rapidly targeted with specific inhibitors in order to control the levels of vasoconstrictors [angiotensin II (AII) and endothelin-1 (ET-1)] and vasodilators [bradykinin (BK) and atrial natriuretic peptide (ANP)], thereby controlling blood pressure. The first class of inhibitors to be developed were against angiotensin-converting enzyme (ACE), recently followed by dual inhibitors of ACE/neprylisin (NEP), NEP/endothelin-converting enzyme (ECE), and finally triple ACE/NEP/ECE inhibitors. The dual and triple inhibitors are defined as vasopeptidase inhibitors (VPI). In addition to their ability to effectively lower blood pressure in hypertensive patients, drugs targeting these enzymes also displayed antiinflammatory and antifibrotic activities. The major point emerging from recent studies undertaken to improve the management of CDs is that the combined action of different therapeutic strategies (ie, simultaneous modulation of several neurohumoral mediators) shows better results than conservative therapeutic approaches. In this review, we historically present the advances made in the comprehension of the different mechanisms of blood pressure regulation and some of the drugs that arose from this understanding.

[1]  Reza Tabrizchi.  SLV-306. Solvay. , 2003, Current opinion in investigational drugs.

[2]  M. Bleich,et al.  The vasopeptidase inhibitor AVE7688 ameliorates Type 2 diabetic nephropathy , 2003, Diabetologia.

[3]  S. De Lombaert,et al.  Antihypertensive and natriuretic effects of CGS 30440, a dual inhibitor of angiotensin-converting enzyme and neutral endopeptidase 24.11. , 1998, The Journal of pharmacology and experimental therapeutics.

[4]  N. Trippodo,et al.  Repression of angiotensin II and potentiation of bradykinin contribute to the synergistic effects of dual metalloprotease inhibition in heart failure. , 1995, The Journal of pharmacology and experimental therapeutics.

[5]  M. Worthley,et al.  Vasopeptidase inhibitors: will they have a role in clinical practice? , 2003, British journal of clinical pharmacology.

[6]  K. Furuya,et al.  The ACE gene polymorphism and cough threshold for capsaicin after cilazapril usage. , 2001, Respiratory medicine.

[7]  R. Busse,et al.  Signaling via the Angiotensin-Converting Enzyme Enhances the Expression of Cyclooxygenase-2 in Endothelial Cells , 2005, Hypertension.

[8]  J. Rouleau,et al.  A variant in XPNPEP2 is associated with angioedema induced by angiotensin I-converting enzyme inhibitors. , 2005, American journal of human genetics.

[9]  V. Herrera,et al.  Sex-specific effects of dual ET-1/ANG II receptor (Dear) variants in Dahl salt-sensitive/resistant hypertension rat model. , 2005, Physiological genomics.

[10]  K. Tanonaka,et al.  Beneficial Effects of Sampatrilat, a Novel Vasopeptidase Inhibitor, on Cardiac Remodeling and Function of Rats with Chronic Heart Failure following Left Coronary Artery Ligation , 2003, Journal of Pharmacology and Experimental Therapeutics.

[11]  E. Fleck,et al.  Regulation and differential expression of neutral endopeptidase 24.11 in human endothelial cells. , 1995, Hypertension.

[12]  A. Stamford,et al.  Renal Effects of SCH 54470: A Triple Inhibitor of ECE, ACE, and NEP , 2007 .

[13]  W A Ray,et al.  Black Americans have an increased rate of angiotensin converting enzyme inhibitor‐associated angioedema , 1996, Clinical pharmacology and therapeutics.

[14]  Peter S Marshall,et al.  Investigation of Bradykinin metabolism in human and rat plasma in the presence of the dual ace/NEP inhibitors GW660511X and omapatrilat , 2002, Journal of peptide science : an official publication of the European Peptide Society.

[15]  M. Cicardi,et al.  Bradykinin and the pathophysiology of angioedema. , 2003, International immunopharmacology.

[16]  P. Daull,et al.  The First Preclinical Pharmacotoxicological Safety Assessment of CGS 35601, a Triple Vasopeptidase Inhibitor, in Chronically Instrumented, Conscious, and Unrestrained Spontaneously Hypertensive Rats , 2006, Drug and chemical toxicology.

[17]  M. Cicardi,et al.  Plasma bradykinin in angio-oedema , 1998, The Lancet.

[18]  M. Greaves,et al.  Angioedema: manifestations and management. , 1991, Journal of the American Academy of Dermatology.

[19]  D. Hoyer,et al.  Potent and selective non-peptidic inhibitors of endothelin-converting enzyme-1 with sustained duration of action. , 2000, Journal of medicinal chemistry.

[20]  J. Schwartz,et al.  Effect of sinorphan, an enkephalinase inhibitor, on plasma atrial natriuretic factor and sodium urinary excretion in cirrhotic patients with ascites. , 1991, The Journal of clinical endocrinology and metabolism.

[21]  Salim Yusuf,et al.  Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. , 1991, The New England journal of medicine.

[22]  L. Opie,et al.  Controversies in hypertension , 2006, The Lancet.

[23]  R. Busse,et al.  New fACEs to the renin-angiotensin system. , 2005, Physiology.

[24]  K. Dickstein,et al.  Effect of single doses of SLV306, an inhibitor of both neutral endopeptidase and endothelin-converting enzyme, on pulmonary pressures in congestive heart failure. , 2004, The American journal of cardiology.

[25]  T. Katagiri,et al.  Association of polymorphisms of the renin–angiotensin system and bradykinin B2 receptor with ACE-inhibitor-related cough , 2002, Journal of Human Hypertension.

[26]  Alain Tomas,et al.  N-[2-(Indan-1-yl)-3-mercapto-propionyl] amino acids as highly potent inhibitors of the three vasopeptidases (NEP, ACE, ECE): In vitro and In vivo activities. , 2002, Bioorganic & medicinal chemistry letters.

[27]  R. Natesh,et al.  Crystal structure of the human angiotensin-converting enzyme–lisinopril complex , 2003, Nature.

[28]  R. Busse,et al.  Angiotensin-Converting Enzyme Is Involved in Outside-In Signaling in Endothelial Cells , 2004, Circulation research.

[29]  N. Trippodo,et al.  Effects of omapatrilat in low, normal, and high renin experimental hypertension. , 1998, American journal of hypertension.

[30]  J. Rouleau,et al.  Vasopeptidase Inhibitors: A New Therapeutic Concept in Cardiovascular Disease? , 2001, Circulation.

[31]  V. Herrera,et al.  Association of ATP1A1 and Dear Single-Nucleotide Polymorphism Haplotypes With Essential Hypertension: Sex-Specific and Haplotype-Specific Effects , 2007, Circulation research.

[32]  A. Adam,et al.  Aminopeptidase P in individuals with a history of angio-oedema on ACE inhibitors , 2002, The Lancet.

[33]  W. Simmons,et al.  Dipeptidyl Peptidase IV Activity in Patients With ACE-Inhibitor-Associated Angioedema , 2002, Hypertension.

[34]  C. Oefner,et al.  A three-dimensional model of endothelin-converting enzyme (ECE) based on the X-ray structure of neutral endopeptidase 24.11 (NEP). , 2001, Protein engineering.

[35]  D. Campbell,et al.  Vasopeptidase Inhibition. A Double-Edged Sword? , 2003 .

[36]  A. Kenny,et al.  Hydrolysis of human and pig brain natriuretic peptides, urodilatin, C-type natriuretic peptide and some C-receptor ligands by endopeptidase-24.11. , 1993, The Biochemical journal.

[37]  F. Winkler,et al.  Structure of human neutral endopeptidase (Neprilysin) complexed with phosphoramidon. , 2000, Journal of molecular biology.

[38]  C. Lang,et al.  Clearance of brain natriuretic peptide in patients with chronic heart failure: indirect evidence for a neutral endopeptidase mechanism but against an atrial natriuretic peptide clearance receptor mechanism. , 1992, Clinical science.

[39]  S. Raharjo,et al.  Dual ECE/NEP Inhibition on Cardiac and Neurohumoral Function During the Transition From Hypertrophy to Heart Failure in Rats , 2005, Hypertension.

[40]  Arco Y Jeng,et al.  CGS 34226, a thiol-based dual inhibitor of endothelin converting enzyme-1 and neutral endopeptidase 24.11. , 2002, Clinical science.

[41]  E. Giroux,et al.  Characterization of a dual inhibitor of angiotensin I-converting enzyme and neutral endopeptidase. , 1994, The Journal of pharmacology and experimental therapeutics.

[42]  R. Henning,et al.  Renoprotective effects of VPI versus ACEI in normotensive nephrotic rats on different sodium intakes. , 2003, Kidney international.

[43]  C. Johnston,et al.  In-vitro and in-vivo inhibition of rat neutral endopeptidase and angiotensin converting enzyme with the vasopeptidase inhibitor gemopatrilat , 2001, Journal of hypertension.

[44]  A. Jeng,et al.  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 , 2004, Journal of cardiovascular pharmacology.

[45]  R. Califf,et al.  Comparison of Omapatrilat and Enalapril in Patients With Chronic Heart Failure: The Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE) , 2002, Circulation.

[46]  P. Daull,et al.  CGS 35601, a triple inhibitor of angiotensin converting enzyme, neutral endopeptidase and endothelin converting enzyme. , 2006, Cardiovascular drug reviews.

[47]  A. Kenny,et al.  Metabolism of neuropeptides. Hydrolysis of the angiotensins, bradykinin, substance P and oxytocin by pig kidney microvillar membranes. , 1987, The Biochemical journal.

[48]  F. Macchi,et al.  A double-blind, placebo-controlled study to assess tolerability, pharmacokinetics and preliminary pharmacodynamics of single escalating doses of Z13752A, a novel dual inhibitor of the metalloproteases ACE and NEP, in healthy volunteers. , 2000, British journal of clinical pharmacology.

[49]  P. Daull,et al.  Triple vasopeptidase inhibition normalizes blood pressure in conscious, unrestrained, and spontaneously hypertensive rats. , 2005, American journal of hypertension.

[50]  P. Mulder,et al.  Sustained Improvement of Cardiac Function and Prevention of Cardiac Remodeling after Long-Term Dual ECE-NEP Inhibition in Rats with Congestive Heart Failure , 2004, Journal of cardiovascular pharmacology.

[51]  J. Schwartz,et al.  Antihypertensive effects of fasidotril, a dual inhibitor of neprilysin and angiotensin-converting enzyme, in rats and humans. , 2000, Hypertension.

[52]  William H. Yang,et al.  Canadian 2003 International Consensus Algorithm For the Diagnosis, Therapy, and Management of Hereditary Angioedema. , 2004, The Journal of allergy and clinical immunology.

[53]  F. Recchia,et al.  Kinin-mediated coronary nitric oxide production contributes to the therapeutic action of angiotensin-converting enzyme and neutral endopeptidase inhibitors and amlodipine in the treatment in heart failure. , 1999, The Journal of pharmacology and experimental therapeutics.

[54]  S. Yusuf,et al.  Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. , 2000 .

[55]  R. Ardaillou,et al.  Characterization of neutral endopeptidase in vascular smooth muscle cells of rabbit renal cortex. , 1993, The American journal of physiology.

[56]  M. Burnier,et al.  Neutral endopeptidase versus angiotensin converting enzyme inhibition in essential hypertension , 1995, Journal of hypertension.

[57]  F. Messerli,et al.  Vasopeptidase inhibition and angio-oedema , 2000, The Lancet.

[58]  M. Fournié-Zaluski,et al.  Dual inhibition of angiotensin-converting enzyme and neutral endopeptidase by the orally active inhibitor mixanpril: a potential therapeutic approach in hypertension. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[59]  A. Adam,et al.  Angiotensin-Converting Enzyme Inhibitor-Associated Angioedema Is Characterized by a Slower Degradation of des-Arginine9-Bradykinin , 2002, Journal of Pharmacology and Experimental Therapeutics.

[60]  Y. Matsumura,et al.  Effects of SA7060, a novel dual inhibitor of neutral endopeptidase and angiotensin-converting enzyme, on deoxycorticosterone acetate-salt-induced hypertension in rats. , 2000, Biological & pharmaceutical bulletin.

[61]  D. Hoyer,et al.  Effects of the ECE/NEP inhibitor CGS 34225 on the big ET-1-induced pressor response and plasma atrial natriuretic peptide concentration in conscious rats. , 2002, Clinical science.

[62]  K. Swedberg,et al.  Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). , 1988, The American journal of cardiology.

[63]  A. Jeng,et al.  Characterization of CGS 31447, a potent and nonpeptidic endothelin-converting enzyme inhibitor. , 1998, Journal of cardiovascular pharmacology.

[64]  E. Mervaala,et al.  Angiotensin II and vascular inflammation. , 2005, Medical science monitor : international medical journal of experimental and clinical research.

[65]  K. Chung,et al.  Pathophysiology and clinical presentations of cough. , 1996, The Journal of allergy and clinical immunology.

[66]  R. Gerzer,et al.  Neutral endopeptidase 24.11 inhibition may not exhibit beneficial haemodynamic effects in patients with congestive heart failure , 1996, European Journal of Clinical Pharmacology.

[67]  B Rubin,et al.  Design of specific inhibitors of angiotensin-converting enzyme: new class of orally active antihypertensive agents. , 1977, Science.

[68]  K. Cooper,et al.  Examination of baseline levels of carboxypeptidase N and complement components as potential predictors of angioedema associated with the use of an angiotensin-converting enzyme inhibitor. , 1997, Archives of dermatology.

[69]  A. Overlack.  ACE inhibitor-induced cough and bronchospasm. Incidence, mechanisms and management. , 1996, Drug Safety.

[70]  D. Brooks,et al.  Mechanism of Vasopeptidase Inhibitor-Induced Plasma Extravasation: Comparison of Omapatrilat and the Novel Neutral Endopeptidase 24.11/Angiotensin-Converting Enzyme Inhibitor GW796406 , 2005, Journal of Pharmacology and Experimental Therapeutics.

[71]  R. Busse,et al.  CK2 Phosphorylates the Angiotensin-Converting Enzyme and Regulates Its Retention in the Endothelial Cell Plasma Membrane , 2002, Circulation research.

[72]  A. Fujimura,et al.  Different Effects of Imidapril and Enalapril on Aminopeptidase P Activity in the Mouse Trachea , 2005, Hypertension Research.

[73]  D. Ganten,et al.  Renal and antihypertensive effects of neutral endopeptidase inhibition in transgenic rats with an extra renin gene. , 1996, American journal of hypertension.