Enzyme ACE inhibitor

Thiazide diuretics have a venerable history as antihypertensive agents until the advent of the angiotensin-converting enzyme (ACE) inhibitors this class of drugs completely dominated first line therapy for hypertension. The size of thi.s market led until surprisingly recently to the syntheses of new sulfonamides related to the thiazides. Preparation of one of the last of these compounds starts by exhaustive reduction of the Diels-Alder adduct from cyclopentadiene and malei-mide (207). Nitrosation of the product (208), followed by reduction of the nitroso group of 209,... 

Hyperkalemia is an excess of potassium in the blood. Clinical symptoms are muscle weakness and cardiac arrhythmias. It is caused by, e.g., hyperaldosteronism and angiotensin-converting enzyme (ACE) inhibitors. 

Until recently, the cardiotonics and a diuretic were the treatment of choice for HE However, other dragp such as the angiotensin-converting enzyme (ACE) inhibitors, and beta blockers have become the treatment of choice during the last several years. See Figure 39-1 for an example of a method of determining treatment for left ventricular systolic dysfunction. See Chapters 23, 42, and 46 for more information on the beta blockers, ACE inhibitors, and diuretics, respectively. 

Angiotensm-converting enzyme (ACE) inhibitors— for example, captopril (Capoten), enalapril (Vasotec), and lismopril (Prinivil)... 

Redshaw S. Angiotensin-converting enzyme (ACE) inhibitors and the design of captopril. In Ganellin CR, Roberts SM, editors. Medicinal chemistry. The role of organic chemistry in drug research, 2nd edition. Fondon Academic Press, 1993. p. 163-85. 

Another important class of pharmaceuticals which is prepared from chiral 2-hydroxy acids is the angiotensin-converting enzyme (ACE) inhibitors. (R)-3-phenylpropionaldehyde cyanohydrin is transformed into the corresponding 2-hydroxy ester which after activation by sulfonylafion reacts with dipetides to give, under inversion of configuration, ACE inhibitors known as prils (Scheme 6). ... 

Azathioprine, mycophenolate mofetil, and enteric-coated MPA are not metabolized through the CYP isozyme system therefore, they do not experience the same DDI profiles as cyclosporine, tacrolimus, and sirolimus. Azathioprine s major DDIs involve allopurinol, angiotensin-converting enzyme (ACE) inhibitors, aminosalicylates (e.g., mesalamine and sulfasalazine), and warfarin.11 The interaction with allopurinol is seen frequently and has clinical significance. Allopurinol inhibits xanthine oxidase, the enzyme responsible for metabolizing azathioprine. Combination of azathioprine and allopurinol has resulted in severe toxicities, particularly myelosuppression. It is recommended that concomitant therapy with azathioprine and allopurinol be avoided, but if combination therapy is necessary, the azathioprine doses must be reduced to one-third or one-fourth of the current dose. Use of azathioprine with the ACE inhibitors or aminosalicylates also can result in enhanced myelosuppression.11 Some case reports exist demonstrating that warfarin s therapeutic effects may be decreased by azathioprine.43-45... 

Enalaprilat and SQ27,519 are angiotensin-converting enzyme (ACE) inhibitors with poor oral absorption. Enalapril and fosinopril are dipeptide and amino acid derivatives of enalaprilat and SQ27,519, respectively [51] (Fig. 10). Both prodrugs are converted via deesterification to the active drug by hepatic biotransformation. In situ rat perfusion of enalapril indicated a nonpassive absorption mechanism via the small peptide carrier-mediated transport system. In contrast to the active parent, enalapril renders enalaprilat more peptide-like, with higher apparent affinity for the peptide carrier. The absorption of fosinopril was predominantly passive. Carrier-mediated transport was not demonstrated, but neither was its existence ruled out. 

DI Friedman, GL Amidon. Passive and carrier-mediated intestinal absorption components of two angiotensin converting enzyme (ACE) inhibitor prodrugs in rats Enalapril and fosinopril. Pharm Res 6(12) 1043-1047, 1989. 

Angiotensin-converting enzyme (ACE) inhibitors. ACE inhibitors not only cause vasodilation (1 TPR), but also inhibit the aldosterone response to net sodium loss. Normally, aldosterone, which enhances reabsorption of sodium in the kidney, would oppose diuretic-induced sodium loss. Therefore, coadministration of ACE inhibitors would enhance the efficacy of diuretic drugs. 

Captopril 678 and enalapril 679 are potent angiotensin converting enzyme (ACE) inhibitors used as antihypertensives. Molecular manipulation based on the enzyme model led to the discovery of some perspective bicyclic structures, for example, cilazapril 680 and compound 681, highly active antihypertensives in vivo. Compound 681 belongs to the most potent conformationally restricted ACE inhibitors and is often used as a model for molecular modeling studies <1996JA8231>. 

For compounds not metabolized by the gut wall, liver, or affected by transporters, a direct relationship between oral absorption and bioavailability should be observed. The calculated oral absorption, using PSA as a measure for passive membrane permeability reflecting the absorption step, relates to the in vivo observed bioavailability for three classes of compounds - angiotensin-converting enzymes (ACE) inhibitors, P-blockers, and calcium antagonists - is shown below [25],... 

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