Captopril structure

The structural relationship of pivopril to the commercially important analogues captopril (51) and enalaprilat (52) is readily apparent. 

Fig. 7. A Zn21 -cyclen derivative (3) with coordinated captopril, and molecular structure of a Znn(cyclen)-N3 bound 1-MeT.

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>. 

One of the hrst angiotensin converting enzyme (ACE) inhibitors was teprotide. It is an antihypertensive drug for use after heart attacks. The active ingredient was isolated from the venom of a South American viper snake. Other well-known ACE inhibitors such as captopril and analopril were developed based on modifications to the venom chemical structures. 

Very recently the protein structures of ACE with the bound inhibitors Lisinopril (Fig. 4) and Captopril were published (101,102). Also the protein structure of the LF from Bacillus anthracis (PDB-Code 1J7N) caused a sensation, which is now available to the public (Fig. 14b) (103). LF is part of the toxic exotoxin complex composed of three distinct proteins (protective antigen PA, the lethal factor LF and the edema factor EF), and is thought to be the most toxic... 

Where more than one chiral centre is present in a molecule there is the possibility of diastereoisomers, e.g. captopril. Another example of a synthetic drug with two chiral centres is labetalol. The number of diastereoisomers arising from n chiral centres is 2"i.e. 2 in the case of labetalol. In the structure shown in Figure 2.5 chiral centres 1 and 2 in structure A have the configurations R and S respectively the enantiomer of this structure (B) has the S and R configurations in centres 1 and 2. In addition there is a pair of enantiomers C and D that are diastereoisomers of the structures A and B, which have the configurations R2R and 16 25 . 

An important class of orally active ACE inhibitors, directed against the active site of ACE, is now extensively used. Captopril and enalapril are examples of the many potent ACE inhibitors that are available. These drugs differ in their structure and pharmacokinetics, but in clinical use, they are interchangeable. ACE inhibitors decrease systemic vascular resistance without increasing heart rate, and they promote natriuresis. As described in Chapters 11 and 13, they are effective in the treatment of hypertension, decrease morbidity and mortality in heart failure and left ventricular dysfunction after myocardial infarction, and delay the progression of diabetic nephropathy. 

---