title: 1,2-Cyclomethylenecarboxylic monoamide hydroxamic derivatives. A novel class of non-amino acid angiotensin converting enzyme inhibitors.
abstract: A series of monoamidic derivatives of cis- and trans-1,2-cyclohexanedicarboxylic and 1,2-cyclopentanedicarboxylic acids bearing either a carboxylic, sulfhydrylic, or hydroxamic group in the side chain were synthesized and evaluated in vitro for their inhibitory activity against angiotensin converting enzyme. The compounds were designed as potential ACE inhibitors of novel structure, assuming that a monoamidic residue of an 1,2-cyclomethylenedicarboxylic acid could be an alternative structure to the acylproline moiety, the carboxyl-terminal portion common to various ACE inhibitors. The most active compounds were found in the hydroxamic derivatives of cyclohexane series; within this series of derivatives a marked increase of potency was caused by alkylation of the amidic nitrogen with a methyl or ethyl group. Therefore enantiomers of the selected hydroxamic derivatives of cis- and trans-1,2-cyclohexanedicarboxylic acid were prepared by two different chiral synthetic routes and evaluated in vitro for their ACE inhibitor potencies. The active enantiomers both of the cis series (21a, 21c) and trans series (16b, 16d) were found to have all R configuration at the C-2 and R or S configuration at the C-1, while in the classical ACE inhibitors S configuration at the terminal carboxylate (corresponding to the C-1 of our compounds) is strictly required for activity. The most potent compound of the series was (1S,2R)-cis-2[[[2-(hydroxyamino)-2-oxoethyl]methylamino]carbonyl] cyclohexanecarboxylic acid (21a) with an IC50 value of 7.0 nM compared with the value of 3.0 nM for captopril. Further 21a was shown to be highly selective and competitive ACE inhibitor. These results indicate that this non-amino acid structure of inhibitors meets the ACE active site requirements for the binding. The binding compatibility of the most active compounds with a model of ACE active site was evaluated by molecular modeling techniques.
authors.affiliation: Laboratori Guidotti S.p.A., Pisa, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Turbanti
authors.forename: G
authors.initials: G
authors.lastname: Cerbai
authors.forename: C
authors.initials: C
authors.lastname: Di Bugno
authors.forename: R
authors.initials: R
authors.lastname: Giorgi
authors.forename: G
authors.initials: G
authors.lastname: Garzelli
authors.forename: M
authors.initials: M
authors.lastname: Criscuoli
authors.forename: A R
authors.initials: AR
authors.lastname: Renzetti
authors.forename: A
authors.initials: A
authors.lastname: Subissi
authors.forename: G
authors.initials: G
authors.lastname: Bramanti
authors.forename: S A
authors.initials: SA
authors.lastname: DePriest
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D003509:Cyclohexanecarboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D006898:Hydroxylamines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D002264:Carboxylic Acids; D003509:Cyclohexanecarboxylic Acids; D006877:Hydroxamic Acids; D006898:Hydroxylamines; C076966:idrapril