Angiotensin-converting enzyme inhibitors availability

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 ... 

Celecoxib is currently indicated for the relief of signs and symptoms of osteoarthritis and rheumatoid arthritis and to reduce the number of adenomatous colorectal polyps in familial adenomatous polyposis as an adjunct to usual care. Celecoxib is at least as effective as naproxen in the symptomatic management of osteoarthritis and at least as effective as naproxen and diclofenac in the symptomatic treatment of rheumatoid arthritis, and it is less likely to cause adverse Gl effects. Celecoxib appears to be effective in the management of pain associated with both of these arthritic conditions, but effectiveness in acute or chronic pain has not been fully demonstrated. Unlike aspirin, celecoxib does not exhibit antiplatelet activity. Concomitant administration of aspirin and celecoxib may increase the incidence of Gl side effects. Another notable potential drug interaction with celecoxib is its ability, like other NSAIDs, to reduce the blood pressure response to angiotensin-converting enzyme inhibitors. A more detailed discussion of the chemical, pharmacological, pharmacokinetic, and clinical aspects of celecoxib is available (81). 

Cyanohydrins are bifunctional molecules and therefore constitute a particularly useful class of compounds for synthetic purposes. A hydroxyl and a nitrile functional group are available for chemical and enzymatic follow-up reactions (Scheme 25.2 [7, 93-95]), resulting in hydroxy carboxylic acids [96-99], carbamates [KXl], hydroxy-amides [101], primary and secondary hydroxyamines [46,102-104], aziridines [105, 106], aminonitriles [107, 108], diamines [108], azidonitriles [108], a-fluoronitriles [109], hydroxy ketones [110], and many more. The (S)-selective H HNL and the (R)-selective PaHNL, in particular are used on large scale either for the s)mthesis of (S)-3-phenoxybenzaldehyde cyanohydrin, a precursor for p5U ethroids, a class of insecticides (R)- and (S)-mandelonitrile, which can be further converted to man-delic acids (R)-chloromandelonitrile, a precursor for an anticoagulant (R)-2-hydroxy-4-phenylbutyronitrile, which serves as intermediate for the production of angiotensin-converting enzyme inhibitors (ACEi) or (R)-2-amino-l-(2-furyl)ethanol [94]. Several HNLs are commercially available as free or immobilized enzymes. 

Conformational restriction has also been used to determine the bioactive conformation of enzyme-inhibitor systems for which no X-ray crystal structure is available. Thorsett et al. (49) synthesized conformationally restricted bicyclic lactam derivatives of the angiotensin converting enzyme (ACE)inhibitors enalapril (20) and enalaprilat (21) (Fig. 15.9) to characterize torsion angles in the bioactive conformation. Analog (22) was used to constrain the torsion angle psi (T ). Flynn et al. 

Angiotensin-II-receptor antagonists (ARBs) are approved for the treatment of hypertension. In addition, irbesartan and losartan are approved for diabetic nephropathy, losar-tan is approved for stroke prophylaxis, and valsartan is approved for heart failure patients who are intolerant of angiotensin-converting enzyme (ACE) inhibitors. The efficacy of ARBs in lowering blood pressure (BP) is comparable with that of other established antihypertensive drugs, with an adverse-effect profile similar to that of placebo. ARBs also are available as fixed-dose combinations with hydrochlorothiazide. 

Angiotensin-converting enzyme (ACE) inhibitors are used for the treatment of high blood pressure, and were designated using the carboxypeptidase structure as a model for Zn " protease action. Captopril is a small, potent, orally available, dipeptidyl inhibitor of ACE. 

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