ACE Inhibitors Drug Design - Drug Design of Keto-ACE and Its Ketomethylene Derivatives

Drug Design of Keto-ACE and Its Ketomethylene Derivatives

It was found that other carbonyl-containing groups such as ketones could substitute for the amide bond that links Phe and Gly in ACE inhibitors. Keto-ACE, first described in 1980, has emerged as a potential lead compound for C-domain specific ACE inhibitors. Keto-ACE, a tripeptide analogue of Phe-Gly-Pro, contains a bulky P₁ and P₂ benzyl ring and was shown to inhibit the hydrolysis of angiotensin I and bradykinin via the C-domain. The synthesis of keto-ACE analogues with Trp or Phe at the P₂’ position led to a marked increase in C-domain selectivity, but the introduction of an aliphatic P₂ group conferred N-domain selectivity. Inhibitory potency may further be enhanced by the incorporation of hydrophobic substituent, such as phenyl group at the P₁’ position. Also P₁’ substituent with S-stereochemistry has been shown to possess greater inhibitory potency than their R-counterparts.

Keto-ACE was used as the basis for the design of ketomethylene derivates. Its analogues contain a ketomethylene isostere replacement at the scissile bond that is believed to mimic the tetrahedron transition state of the proteolytic reaction at the active site. The focus was on a simple tripeptide Phe-Ala-Pro, which in earlier enzyme assays has shown inhibition activity. Replacement of alanine with glycin gave a tripeptide with 1/14th of the inhibition activity of Phe-Ala-Pro. The benzoylated derivative of Phe-Gly-Pro, Bz-Phe-Gly-Pro, was twice as active. To reduce the peptidic nature of ketomethylene inhibitors the P₁’ and P₂’ substituent may be cyclized to form a lactam, where there is a correlation between the inhibitory potency and the ring size. In 2001 it was postulated that a substitution α to nitrogen and making of 3-methyl-substituted analog of A58365A, a pyridone acid isolated from the fermentation broth of the bacterium Streptomyces chromofuscus with ACE inhibitory activity, might influence the level of biological activity by steric or hydrophobic effect, and/or by preventing reactions at C3. Also it was noticed during the synthetic work on A58365A that potential precursor were sensitive to oxidation of the five-membered ring and so the 3-methyl analogue might be more stable in this respect.