Lisinopril inhibitors

Fig. 14. Active site (a) of the angiotensin converting enzyme (ACE) with Lisinopril inhibitor bound to zinc(II) (PDB-Code 1086) (101), (b) of the lethal factor of Bacillus anthracis (PDB-Code 1J7N) (103).

Most ACE inhibitors are prodrugs, with the exceptions of captopril, lisinopril, and ceranapril. Prodrugs exert improved oral bioavailability, but need to be converted to active compounds in the liver, kidney, and/or intestinal tract. In effect, converting enzyme inhibitors have quite different kinetic profiles with regard to half time, onset and duration of action, or tissue penetration. 

Swaan, P. W., Stenhouwer, M. C., Tukker, J., Molecular mechanism for the relative binding affinity to the intestinal peptide carrier. Comparison of three ACE-inhibitors enalapril, enalaprilat, and lisinopril, Biochim. Biophys. Acta 1995, 3236, 31-38. 

All 10 ACE inhibitors available in the United States can be dosed once daily for hypertension except captopril, which is usually dosed two or three times daily. The absorption of captopril (but not enalapril or lisinopril) is reduced by 30% to 40% when given with food. 

As angiotensin-converting enzyme inhibitors influence protein excretion in renal disease, Gansevoort et al. (G2) and Keilani et al. (K10) investigated serum Lp(a) concentrations in patients treated with Lisinopril resp. fosinopril and detected a reduction. 

P. W. Swaan, M. C. Stehouwer, J. J. Tukker, Molecular Mechanism for the Relative Binding Affinity to the Intestinal Peptide Carrier. Comparison of Three ACE-Inhibitors Enalapril, Enalaprilat and Lisinopril , Biochim. Biophys. Acta 1995, 1236, 31-38. 

The structure with an inhibitor, lisinopril, revealed the exact nature of the binding of the drug to the active site. With this detailed analysis, more efficacious drugs are expected to be developed to bind to the active site (C terminal, such as RXPA380) and control blood pressure. 

Captopril (Capoten ), Enalapril and Lisinopril (Fig. 13) are examples of ACE inhibitors that are rather successful as pharmaceutical drugs against hypertension. In most cases these inhibitors are bound via zinc binding groups (ZBGs) such as thiolates, carboxylates or hydroxamates to the zinc(II) center of the active site. 

Very recently the protein structures of ACE with the bound inhibitors Lisinopril (Fig. 4) and Captopril were published (101,102). Also the protein structure of the LF from Bacillus anthracis (PDB-Code 1J7N) caused a sensation, which is now available to the public (Fig. 14b) (103). LF is part of the toxic exotoxin complex composed of three distinct proteins (protective antigen PA, the lethal factor LF and the edema factor EF), and is thought to be the most toxic... 

Zestril contains lisinopril, an angiotensin-converting enzyme inhibitor. Angiotensin-converting enzyme inhibitors tend to retain potassium, thereby counteracting the potassium loss caused by the thiazide diuretic bendroflumethiazide. 

Concomitant administration of methotrexate and Voltarol, a proprietary preparation of diclofenac, a non-steroidal anti-inflammatory drug, may result in accumulation of methotrexate as its excretion is reduced. The use of diclofenac and diuretics such as bendroflumethiazide may increase the risk of nephrotoxicity. Concomitant use of alcohol and an angiotensin-converting enzyme inhibitor such as lisinopril (Zestril) may result in an enhanced hypotensive effect. Alcohol and the benzodiazepine diazepam (Valium) may result in enhanced sedation. 

Lisinopril is an angiotensin-converting enzyme (ACE) inhibitor and ACE inhibitors should be avoided during pregnancy. ACE inhibitors may adversely affect fetal and neonatal blood pressure control and renal function. They may also cause neonatal skull defects. 

Undesired effects. The magnitude of the antihypertensive effect of ACE inhibitors depends on the functional state of the RAA system. When the latter has been activated by loss of electrolytes and water (resulting from treatment with diuretic drugs), cardiac failure, or renal arterial stenosis, administration of ACE inhibitors may initially cause an excessive fall in blood pressure. In renal arterial stenosis, the RAA system may be needed for maintaining renal function and ACE inhibitors may precipitate renal failure. Dry cough is a fairly frequent side effect, possibly caused by reduced inactivation of kinins in the bronchial mucosa. Rarely, disturbances of taste sensation, exanthema, neutropenia, proteinuria, and angioneurotic edema may occur. In most cases, ACE inhibitors are well tolerated and effective. Newer analogues include lisinopril, perindo-pril, ramipril, quinapril, fosinopril, benazepril, cilazapril, and trandolapril. 

Other interesting applications of the ophcally active cyanohydrins obtained by (R)-oxynitrilase-catalyzed processes are the produchon of the blockbuster clopido-grel (Scheme 10.23) [52], and the angiotensin-converhng enzyme inhibitors enala-pril and lisinopril (Scheme 10.24) [53, 54]. 

Most of the so far available ACE-inhibitors with the exception of captopril and lisinopril are prodrugs, which are converted in the liver into an active metabolite. 

While essentially all ACE inhibitors have a similar mechanism of action and therefore exhibit similar efficacy in the treatment of hypertension and congestive heart failure, these drugs differ slightly in their pharmacokinetic profiles. Enalapril, lisinopril, and quinapril are excreted primarily by the kidney, with minimal liver metabolism, while the other prodrug compounds are metabolized by the liver and renally excreted. Thus, in patients with renal insufficiency, the half-life of renally excreted ACE inhibitors is prolonged. In addition, patients with impaired liver func-... 

The success of enalapril led to a variety of other additional dicarboxylate inhibitors. The first of these was lisinopril (5.138). This agent was developed at the same time as... 

Angiotensin converting ENZYME (ACE) inhibitors captopril cilazapril enalapril maleate fosinopril sodium lisinopril... 

With the exception of captopril and lisinopril, all ACE inhibitors are prodrugs which have to be activated metabolically after absorption from the gut. Although there are differences in the... 

Enalapril is an oral prodrug that is converted by hydrolysis to a converting enzyme inhibitor, enalaprilat, with effects similar to those of captopril. Enalaprilat itself is available only for intravenous use, primarily for hypertensive emergencies. Lisinopril is a lysine derivative of enalaprilat. Benazepril, fosinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril are other long-acting members of the class. All are prodrugs, like enalapril, and are converted to the active agents by hydrolysis, primarily in the liver. 

Captopril s pharmacokinetic parameters and dosing recommendations are set forth in Table 11-2. Peak concentrations of enalaprilat, the active metabolite of enalapril, occur 3-4 hours after dosing with enalapril. The half-life of enalaprilat is about 11 hours. Typical doses of enalapril are 10-20 mg once or twice daily. Lisinopril has a half-life of 12 hours. Doses of 10-80 mg once daily are effective in most patients. All of the ACE inhibitors except fosinopril and moexipril are eliminated primarily by the kidneys doses of these drugs should be reduced in patients with renal insufficiency. 

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