UK 69578candmatrilat

candoxatrilat (8.62, UK 69578), where the (+)-enantiomer is 30-fold more potent than the (-)-enantiomer. Phosphoramidon, a phosphoryl dipeptide of microbial origin, inhibits both thermolysin and MEP and has formed the basis for the development of specific phosphoryl inhibitors of MEP. A phosphonic acid dipeptide containing a P-alanine residue (8.63) has shown selectivity for MEP. A-Phosphonomethyl dipeptide inhibitors such as CGS 24592 (8.64) were based on the observation that the ACE inhibitors fosinopril (8.57) and ceranapril (8.58) tend to be longer acting than other carboxylic acid or thiol-containing analogues. It was noted that CGS 24592 (8.64)

underwent a very slow hydrolysis in bicarbonate solution to the derivative (8.65) which exhibited unexpected inhibitory potency for MEP (IC50=15 nM). The structure represented a significant o- O o o- O o

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