and P 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 P’ position led to a marked increase in C-domain selectivity, but the introduction of an aliphatic P group conferred N-domain selectivity. Inhibitory potency may further be enhanced by the incorporation of hydrophobic substituent, such as phenyl group at the P’ position. P’ substituents with S-stereochemistry have also been shown to possess greater inhibitory potency than their R-counterparts.
’ and P’ 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. It was also noticed during the synthetic work on A58365A that potential precursors were sensitive to oxidation of the five-membered ring and so the 3-methyl analogue might be more stable in this respect.