Description
Cilastatin is an inhibitor of dipeptidase (dehydropeptidase I), a renal dipeptidase. It inhibits human renal dipeptidase (K
i = 0.7 μM), porcine dipeptidase (IC
50 = 0.11 μM), and bacterial metallo-β-lactamase CphA from
A. hydrophila (IC
50 = 178 μM). Cilastatin (200 μg/ml) protects primary porcine renal proximal tubular epithelial cells from nephrotoxicity and apoptosis induced by vancomycin . In a mouse model of systemic infection, cilastatin in combination with imipenem protects mice from
S. aureus,
E. coli, and
P. aeruginosa infection. Cilastatin was designed to inhibit renal metabolism of imipenem and prolong its half-life. Formulations containing cilastatin in combination with imipenem have been used to treat susceptible bacterial infections.
Chemical Properties
White to Light-Yellow Crystalline Powder
Uses
Prevents renal metabolism of penem and carbapenem antibiotics by specific and reversible dehydropeptidase I inhibition. Antibacterial adjunct
Uses
Cilastatin is used for treating diseases caused by polyresistant Gram-negative microorganisms and serious complex infections, including infection of S. aureus. Because of its strong
activity against anaerobic bacteria, cilastatin is effective in monotherapy of intraabdominal infections. It is used for infectious diseases of the lower respiratory tract, urinary tract,
gynecological infections, bacterial septicemia, and infections of the bones, skin, and so on.
Definition
ChEBI: Cilastatin is the thioether resulting from the formal oxidative coupling of the thiol group of L-cysteine with the 7-position of (2Z)-2-({[(1S)-2,2-dimethylcyclopropyl]carbonyl}amino)hept-2-enoic acid. It is an inhibitor of dehydropeptidase I (membrane dipeptidase, 3.4.13.19), an enzyme found in the brush border of renal tubes and responsible for degrading the antibiotic imipenem. Cilastatin is therefore administered (as the sodium salt) with imipenem to prolong the antibacterial effect of the latter by preventing its renal metabolism to inactive and potentially nephrotoxic products. Cilastatin also acts as a leukotriene D4 dipeptidase inhibitor, preventing the metabolism of leukotriene D4 to leukotriene E4. It has a role as a protease inhibitor, an EC 3.4.13.19 (membrane dipeptidase) inhibitor, a xenobiotic and an environmental contaminant. It is a non-proteinogenic L-alpha-amino acid, a L-cysteine derivative, an organic sulfide and a carboxamide. It is a conjugate acid of a cilastatin(1-).
Synthesis
Cilastatin, (Z)-7-[(2-amino-2-carboethoxyethyl)thio]-2-[[2,2-dimethylcyclopropyl) carbonyl] amino]-2-heptenoic acid (32.1.3.6), is synthesized from the ethyl ester of
1,3-dithian-2-carboxylic acid (which is ethyl glyoxylate, protected at the aldehyde group
with 1,3-propanedithiol), which is alkylated by 1,5-dibromopentane in the presence of
sodium amide, forming the ethyl ester of 7-bromo-2-[2-(1,3-dithiano)]hepthanoic acid
(32.1.3.2). Oxidative hydrolysis of this product with N-bromosuccinimide in a mixture of
acetonitrile¨Cwater solvents leads to the formation of the ethyl ester of 7-bromo-|á-ketoheptanoic acid (32.1.3.3). Acidic hydrolysis of this product using hydrogen bromide in acetic
acid gives 7-bromo-|á-ketoheptanoic acid (32.1.3.4). This is reacted with 2,2-dimethylcyclopropancarboxylic acid amide to form the corresponding enamide, (Z)-7-bromo-2-(2,
2-dimethylcycloprotancarboxamido)-2-heptenoic acid (32.1.3.5). The resulting product is
used for S-alkylation of L-cysteine, which results in the production of the desired cilastatin
(32.1.3.6).
