Angiotensin converting enzyme structure

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. 

Imatinib mesylate (Gleevec, Novartis), zanamivir (Relenza, GlaxoSmithKline), and oseltamivir (Tamiflu, Roche) are examples of drugs (Exhibits 3.11 and 3.7) that show the successful contributions of rational drug design. For example, the X-ray structure of angiotensin converting enzyme (ACE) has been reported (see Exhibit 11.2), and this may pave the way for more effective ACE inhibitors to be developed for the treatment of hypertension and heart disorders. 

Sources (1) Natesh R, Schwager SL, Sturrock ED, Acharya KR. Crystal structure of the human angiotensin-converting enzyme-lisinopril complex, Nature 421 551-554 (2003). Used with permission. (2) Turk B. Targeting proteases, successes, failures and future prospects. Nature Reviews Drug Discovery 5 785-799 (2006). 

Natesh R, Schwager SL, Sturrock ED, Acharya KR. Crystal structure of the human angiotensin-converting enzyme-Usinopril complex, Nature 421 551-554 (2003). 

Mayer, D., Naylor, C.B., Motoc, I., Marshall, G.R. Aunique geometry of the active site of angiotensin-converting enzyme consistent with structure-activity studies./. Comput.-Aided Mol. Des. 1987, 3(1), 3-16. 

Figure 6. Superimposition of the crystai structures of the cataiytic domains of LTA4 hydrolase (biue), angiotensin-converting enzyme (red) and thermoiysin (yeiiow), each with bound zinc ion (coioured accordingiy).

With both enantiomers of le in hand, the asymmetric synthesis of (S)-N-acetylindoline-2-carboxylate 33 was carried out, this being a key intermediate in the synthesis of the angiotensin-converting enzyme (ACE) inhibitor 34 (Scheme 5.18) [7e], The structure and stereochemical integrity of 33 was simultaneously constructed by the asymmetric alkylation of 2 with o-bromobenzyl bromide in the presence of (R,R)-le, and subsequent hydrolysis and N-acetylation afforded 32 in 86% yield with 99% ee. According to the Buchwald procedure, almost enantiopure 32 was efficiently converted to 33 (94%, 99% ee) [7e],... 

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