title: Novel ketomethylene inhibitors of angiotensin I-converting enzyme (ACE): inhibition and molecular modelling.
abstract: 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. Ki 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.
authors.affiliation: Division of Medical Biochemistry, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory 7925, Cape Town, South Africa.
authors.forename: Pierre
authors.initials: P
authors.lastname: Redelinghuys
authors.forename: Aloysius T
authors.initials: AT
authors.lastname: Nchinda
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
authors.forename: Edward D
authors.initials: ED
authors.lastname: Sturrock
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D003198:Computer Simulation; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D007703:Peptidyl-Dipeptidase A / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D007703:Peptidyl-Dipeptidase A