Angiotensin converting enzyme dual inhibitors

Combination studies Dual blockade of the renin-angiotensin-aldosterone system by combined use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists may provide more renal protection than monotherapy in chronic kidney disease. In 45 patients with chronic kidney disease who took either enalapril 20 mg/day or candesartan 16 mg/ day for 16 weeks followed by treatment, with incremental dosing of enalapril (target... 

Figure 17.5 The dual vasodilatoiy effect of inhibitors of the angiotensin-converting enzyme (ACE). The ACE inhibitors not only inhibit ACE but also the kininase which degrades bradykinin. (See also Chapter 22).

Robl JA, Sun C-Q et al (1997) Dual metalloprotease inhibitors mercaptoacetyl-based fused heterocyclic dipeptide mimetics as inhibitors of angiotensin-converting enzyme and neutral endopeptidase. J Med Chem 40 1570-1577... 

JA Robl, C Sun, J Stevenson, DE Ryono, LM Simpkins, MAP Cimarusti, T Dejneka, WA Slusarchyk, S Chao, L Stratton, RN Misra, MS Bednarz, MM Asaad, HS Cheung, BE Aboa-Offei, PL Smith, PD Mathers, M Fox, TR Schaeffer, AA Seymour, NC Trippodo. Dual metalloprotease inhibitors mercaptoacetyl-based fused heterocyclic dipeptide mimetics as inhibitors of angiotensin-converting enzyme and neutral endopeptidase. J Med Chem 40 1570-1577, 1997. 

With the exception of S-metolachlor, all the molecules listed under the column Final Target are used in pharmaceutical formulations. Dilitiazem is a Ca2+ antagonist, while Cilazapril is an angiotensin-converting enzyme inhibitor. Levofloxacin is an antibacterial, and cilastatin is used as an in vivo stabilizer of the antibiotic imipenem. S-metolachlor is a herbicide sold under the trade name of DUAL MAGNUM. Although the structures of the final targets are more complex than those of the intermediates, enantioselective syntheses of the intermediates are the most crucial steps in the complex synthetic schemes of these molecules. 

Mixanpril, N-[(2S,3 R)-2-benzoylthiometh-yl-3-phenylbutanoyl]-L-alanine, a dual inhibitor for the neutral endopeptidase-24.11 (NEP) and the angiotensin-converting enzyme (ACE). The orally administerable mixanpril is important for the treatment of high blood pressure and cardiac defects [S. Turcaud et al., Bioorg. Med. Chem. Lett. 1995, 5, 1893]. 

M.-C. Fournie-Zaluski, P. Coric, S. Turcaud, N. Rousselet, W. Gonzalez, B. Barbe, I. Pham, N. Jullian, J.-B. Michel, and B. P. Roques, J. Med. Chem., 37, 1070 (1994). New Dual Inhibitors of Neutral Endopeptidase and Angiotensin-Converting Enzyme Rational Design, Bioavailability, and Pharmacological Responses in Experimental Hypertension. See also references therein. 

Stanton, J. L., Sperbeck, D. M., Trapani, A. J., Cote, D., Sakane, Y., Berry, C. J., Ghai, R. D. Heterocychc lactam dmvatives as dual angiotensin converting enzyme and neutral endt ptidase 24.11 inhibitors. J. Med. Chem. 1993, 36,3829-3833. 

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