85394-14-5Relevant articles and documents
Inhibition of the Mammalian β-Lactamase Renal Dipeptidase (Dehydropeptidase-I) by (Z)-2-(Acylamino)-3-substituted-propenoic Acids
Graham, Donald W.,Ashton, Wallace T.,Barash, Louis,Brown, Jeannette E.,Brown, Ronald D.,et al.
, p. 1074 - 1090 (1987)
The title enzyme deactivates the potent carbapenem antibiotic imipenem in the kidney, producing low antibiotic levels in the urinary tract.A series of (Z)-2-(acylamino)-3-substituted-propenoic acids (3) are specific, competitive inhibitors of the enzyme capable of increasing the urinary concentration of imipenem in vivo.Many of the compounds were prepared in one step from an α-keto acid and a primary amide.The optimum R2 groups are 2,2-dimethyl, -dichloro, and -dibromocyclopropyl.With R2 = 2,2-dimethylcyclopropyl (DMCP), a wide variety of R3 groups including alkyl, oxa- and thiaalkyl, and alkyl groups containing acidic, basic, and neutral substituents give effective inhibitors with Ki values of 0.02-1 μM and a range of pharmacokinetic properties.By resolution of enantiomers and X-ray crystallography, the enzyme-inhibitory activity of the DMCP group was found to reside with the 1S isomer.The cysteinyl compound 176 (cilastatin, MK-0791) has the desired pharmacological properties and has been chosen for combination with imipenem.
