Angiotensin-converting enzyme inhibitors development

Medications can increase the risk of hyperkalemia in patients with CKD, including angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, used for the treatment of proteinuria and hypertension. Potassium-sparing diuretics, used for the treatment of edema and chronic heart failure, can also exacerbate the development of hyperkalemia, and should be used with caution in patients with stage 3 CKD or higher. 

Attempts to counteract tolerance development include the use of thiols such as N-acetylcysteine, antioxidants such as vitamin C and vitamin E, and angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists. Other approaches to decreasing the development of tolerance include intermittent therapy... 

The next example originates from our own laboratory Two potential intermediates for the angiotensin-converting enzyme inhibitor benazepril can be synthesized using cinchona modified noble metal catalysts (3). While the hydrogenation of the a-ketoester has been developed and scaled-up into a production process (10-200 kg scale, chemical yield >98%, ee 79-82%), the novel enantioselective hydrodechlorination reaction (see Section in) could be a potential alternative to the established synthesis where the racemic a-bromobenzazepinon is used [75]. At the moment both selectivity and productivity of the catalyst are too low and substitution reactions occur less readily with the chloro analog. 

By analogy with the above reactions that use 0- and IV-nucleophiles, it has been shown that ring opening of Af-Boc p-lactams can be achieved by reaction with metallated carbon nucleophiles. For instance, Baldwin developed the reaction of a-lithiated sulfones, Scheme 30, with p-lactams, such as 89, to provide access to y-keto a-amino esters 90, after desulfonation of the resulting intermediates. In particular, the angiotensin converting enzyme inhibitor WF-10129 91 has been synthesized by this route [97]. 

Today, captopril (Capoten ) ranks among the most frequently used drugs in the treatment of hypertension. Enalapril (Xanef ) has been commercially available since 1985 as a second ACE inhibitor. The discovery of captopril started an avalanche of research into the synthesis of angiotensin-converting enzyme inhibitors. Some new developments should be mentioned at this point ... 

Further replacements of resolution by enantioselective hydrogenation routes have been developed in the syntheses of cilazapril (15) [ 14] (an angiotensin converting enzyme inhibitor the active ingredient of the antihypertensive Inhib-... 

ACE inhibitor. Angiotensin-converting enzyme inhibitor. A treatment for hypertension. The ace of hearts in drug development s game of poker. 

Angiotensin-converting enzyme inhibitors are effective in the treatment of hypertension and congestive heart failure. ACE inhibitors also prevent bra-dykinin metabolism and, as a result, may produce the side effect of cough and angioedema. Many of the known ACE inhibitors were developed without the aid of computational chemistry techniques. However, a number of studies have used computational methods to design mimics of other nonpeptidic ACE inhibitors. 

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