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Pierre Redelinghuys, Aloysius T. Nchinda, Kelly Chibale, Edward D. Sturrock

Novel ketomethylene inhibitors of angiotensin I-converting enzyme (ACE): inhibition and molecular modelling

Keywords: Kinetics, molecular modelling, physico-chemical characterisation, protease

Inhibition of angiotensin I-converting enzyme (ACE) has become an effective strategy in the treatment of hypertension and cardiovascular disease. Keto-ACE, a previously described C-domain selective ACE inhibitor, was used as the basis for the design, synthesis and molecular modelling of a series of novel ketomethylene derivatives for which ACE inhibition profiles and structural characterisation are reported. K_i determinations indicated that the introduction of a bulky aromatic tryptophan at the P₂? position of keto-ACE significantly increased selectivity for the C-domain, while an aliphatic P₂ Boc group conferred N-domain selectivity. These data were supported by the potential energies of the compounds docked with the C- and N-domains of ACE.

Biological Chemistry, Walter de Gruyter

Print ISSN: 1431-6730
Volume: 387, 04/2006
Pages: 461 - 466

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