Medicines Enalapril

The initial synthetic route employed by the medicinal chemistry group is straightforward a moderately diastereoselective reductive amination between ethyl-2-oxo-4-phenylbutyrate (13) and alanyl-proline (14) generated a 1.6 1 mixture of diastereomers favoring the desired (5,5,5)-enantiomer (Scheme 10.2). Fractional recrystallization afforded enalapril as the maleate salt (Harris et al., 1983 Wyvratt et al., 1984). Although requiring only one synthetic step, the diastereoselectivity of the process is poor, reducing the overall yield. 

SAVE = Survival and Ventricular Enlargement Trial AIRE = Acute Infarction Ramipril Efficacy study CONSENSUS = Cooperative New Scandinavian Enalapril Survival Study. References Rutherford J D et al 1994 Effects of captopril on ischemic events after myocardial infarction. Results of the Survival and Ventricular Enlargement trial. SAVE Investigators. Circulation 90 1731-1738. AIRE Study Investigators 1993 Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 342 821-828. Swedberg K P et al 1992 Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction. New England Journal of Medicine 327 678-684. 

SOLVD = Studies of Left Ventricular Dysfunction. The SOLVD Investigators 1991 Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. New England Journal of Medicine 325 293-302. 

Anon. 1995 Controlled clinical evaluation of enalapril in dogs with heart failure results of the Cooperative Veterinary Enalapril Study Group. Journal of Veterinary Internal Medicine 9 243-252 Anon. 1999 Practice parameters for hemodynamic support of sepsis in adult patients In sepsis. Task Force of the American Coliege of Critical Care Medicine, Society of Criticai Care Medicine. Criticai Care Medicine 27 639-660... 

Sleeper M, McDonnell S, Reef V 2000 Enalapril therapy in 12 pony stallions. Journal of Veterinary Internal Medicine 14 365... 

ACE inhibitor drugs were developed by modelling interaction with the active site of the enzyme of a snake-venom-derived bradykinin-potentiating peptide, and from this the necessary structure of non-peptide inhibitors was inferred. The first such ACE inhibitor used medicinally was caplopril. Later examples in clinical use include cilazapril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, trandolapril. Several ACE inhibitors are now administered clinically as prodrugs - which have good bioavailability, but are inactive in their own right. They are then converted to the active molecule in vivo, usually by esterases (e.g. enalapril to enalaprilat. and ramipril to ramiprilat). 

The manufacture of fine chemicals, particularly drugs, fragrances, and flavors, is undergoing a major revolution now as a result of the capability of chemists to prepare these chemicals, mainly drugs, in their purest isomeric forms (as stereoisomers). This shift to pure forms has been described by Brown in the following words (1990) (see also Deutsch, 1991) A mixture of stereoisomers in a medicine will (now) need to be justified just the same way as any other mixture of compounds. Indeed, in the United States today (as in many other advanced countries), the use of pure enantiomeric forms is practically a requirement since extensive justification is needed to continue with racemates (FDA, 1992). As a consequence, the combined sales of the chiral top ten drugs (ammoxydllin, enalapril, ampicillin, captopril, pravastatine, diltiazem, ibuprofen, lovastatin, naproxen, and fluoxetine) in 1994 amounted to more than 16 billion dollars (Sheldon, 1996). (Of these, ibuprofen and fluoxetine are still sold as racemates.)... 

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