Enalapril

Sample preparation Finely powder tablets, wei out amount equivalent to 20 mg enalapril maleate, suspend in 100 mL mobile phase, filter, inject a 5 piL aliquot. 

Mobile phase MeCN water 20 80 adjusted to pH 3.8 with acetic acid Flow rate 1 Injection volume 5 

Sample preparation Dissolve tablets in MeCN l mM pH 2 KH2PO4 50 50, centrifuge, inject a 50 p-L aliquot of the supernatant. 

Mobile phase MeCN buffer 35 65 (Buffer was 1 mM KH2PO4 adjusted to pH 2 with phosphoric acid.) 

Column temperature 40 Flow rate 2.5 Injection volume 50 Detector UV 215 

Molecular formula CzoH sNjOs Molecular weight 376.5 

In their early efforts to apply the by-product design to ACE, Patchett and Maycock had synthesized only succinylproline, based on the findings of Byers and Wolfenden that benzylsuccinate was superior to ben-zylglutamate as an inhibitor of carboxypeptidase A. Similar active site topologies were assumed for these two enzymes. Evidently this was not the case, since Cushman et al. reported in 1977 (96) that glutarylpro-line (compound 6 Table II.) was more active than compound 5 (Table 

To improve the oral properties of enalaprilat, Patchett and colleagues turned to a prodrug approach. Esters were made of only one and of both carboxyls, and fortunately only esters of the N-carboxyalkyl group were needed for good oral absorption. When the proline carboxyl is esterified, the resultant inhibitor would have been difficult to formulate, since closure to a diketopiperazine easily takes place. Although various esters were tried, none were clearly superior to the ethyl ester 20 (Table IV). 

Initial blood pressure lowering studies of compound 20 in rats and dogs have been summarized by Sweet, Gross and co-workers (123, 125). After thorough study of its in vivo properties, compound 20 as its maleate salt entered clinical studies as MK-421, with the generic name enalapril. 

To account for the good oral activity of enalapril, attention was drawn to the fact that enalaprilat is an anionic zwitterion at physiological pH (pffa s 2.8, 3.5 and 7.6), whereas only the carboxyl of enalapril is ionized (pKa s 3.0 and 5.4) (118,120). The possibility was considered that enalapril is absorbed from the intestine, as are bile acids and other carboxyl-containing compounds including the nonsteroid anti-inflammatory drugs. Later, Amidon and colleagues published data supporting peptide transport in the oral absorption of enalapril (126,127). 

As a prodrug, enalapril is essentially inactive as an ACE inhibitor. Thus, it must be enzymatically converted to enalaprilat, and liver homogenates of rats, dogs, rhesus monkeys, and humans have that capacity (128). In humans and in all nonhuman species except the rhesus monkey, deesterification is the only metabolism which is observed. In monkeys, a small amount of the desproline metabolite of enalaprilat has been detected (128). Absorption of enalapril is reported to be 39% in rats, 64% in dogs, and 60-70% in humans (128). 

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ACE inhibitors can be administered with diuretics (qv), cardiac glycosides, -adrenoceptor blockers, and calcium channel blockers. Clinical trials indicate they are generally free from serious side effects. The effectiveness of enalapril, another ACE inhibitor, in preventing patient mortaUty in severe (Class IV) heart failure was investigated. In combination with conventional dmgs such as vasodilators and diuretics, a 40% reduction in mortaUty was observed after six months of treatment using 2.5—40 mg/d of enalapril (141). However, patients complain of cough, and occasionally rash and taste disturbances can occur. 

Folic acid deficiency Hyperthermia Phenylketonuria Rheumatic disease Virilizing tumors Drugs and chemicals Androgenic chemicals Angiotensin-converting enzyme inhibitors Captopril, enalapril Antibiotics... 

The synthesis of enalapril follows the normal course tor such compounds in that L alanyl-L prolme (27) was reductively alkylated with ethyl 2-oxo 4 phenylbutyiate (26) using sodium cyanoborohydnde as the reducing agent (catalytic reduction may also be used) The product is... 

Spirapril (37) is a clinically active antihypertensive agent closely related structurally and mechanistically to enalapril. Various syntheses are reported with the synthesis of the substituted proline portion being the key to the methods. This is prepared fkim l-carbobenzyloxy-4-oxopro-line methyl ester (33) by reaction with ethanedithiol and catalytic tosic acid. The product (34) is deprotected with 20% HBr to methyl l,4-dithia-7-azospiro[4.4 nonane-8-carboxylate (35), Condensation of this with N-carbobenzyloxy-L-alanyl-N-hydroxysuccinate leads to the dipeptide ester which is deblocked to 36 by hydrolysis with NaOH and then treatment with 20% HBr. The conclusion of the synthesis of spirapril (37) follows with the standard reductive alkylation [11]. 

Some workers avoid delay. Pai)adium-on-carbon was used effectively for the reductive amination of ethyl 2-oxo-4-phenyl butanoate with L-alanyl-L-proline in a synthesis of the antihyperlensive, enalapril maleate. SchifTs base formation and reduction were carried out in a single step as Schiff bases of a-amino acids and esters are known to be susceptible to racemization. To a solution of 4,54 g ethyl 2-oxO 4-phenylbutanoate and 1.86 g L-alanyl-L-proline was added 16 g 4A molecular sieve and 1.0 g 10% Pd-on-C The mixture was hydrogenated for 15 hr at room temperature and 40 psig H2. Excess a-keto ester was required as reduction to the a-hydroxy ester was a serious side reaction. The yield was 77% with a diastereomeric ratio of 62 38 (SSS RSS)((55). 

More than 15 ACE inhibitors are presently available. They belong to three different chemical classes sul-fhydryl compounds such as captopril, carboxyl compounds such as enalapril, and phopshorus compounds... 

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

Hydroserpine 2 Tablets—hydrochbrothiazide, reserpine Hyzaar—hydrochlorothiazide, losartan potassium Inderide—hydrochlorotliiazide, propranolol HC1 Inderide LA—hydrochlorotliiazide, propranolol HC1 Lexxel Extended-Release—enalapril maleate, felodipine Lopressor—hydrochlorothiazide, metoprolol Lotensin HCT—hydrochlorothiazide, benazepril Lotrel—amlodopine, benazepril... 

Teczem EIxtended-Release—diltiazem maleate, enalapril maleate... 

Uniretic—hydrochlorotliiazide, moexipril HC1 Vaseretic—hydrochlorotliiazide, enalapril maleate Zestoretic—hydrochlorotliiazide, lisinopril Ziac—hydrochlorothiazide, bisoprolol fumarate... 

CSH14N2O3 13485-59-1) see Enalapril L-alanyl-L-proline benzyl ester... 

C 7H jBrN3 65676-22-4) see Brompheniramine bromo(2-phenylethyl)magnesium (CjH BrMg 32 77-S9-2) see Enalapril (4-bromophenyl)hydrazine monohydrochloride (C4HgBrClN2 622-88-8) see Bromazepam... 

C2( H,jN205 35084-69-6) see Enalapril (5)-a-[[(l,l-dimethylethoxy)carbonyl]aminu]benzeneace-tic acid methyl ester... 

Bain, S.C., Le Guen, C.A., Lunec, J. and Barnett, A.H. (1991). Comparison of the free radical scavenging activity of captopril versus enalapril a three-month trial in vivo study in hypertensive diabetic patients. J. Human Hypertens. 5, 511-515. 

The nitrate-hydralazine combination was first shown to improve survival compared to placebo.27 Subsequently, the combination of isosorbide dinitrate 40 mg and hydralazine 75 mg, both given four times daily, was compared to the ACE inhibitor enalapril.28 Enalapril produced a 28% greater decrease in mortality. Therefore, the combination is considered a third-line vasodilatory option for patients truly intolerant of ACE inhibitors and ARBs. 

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