Thienamycin Imipenem

The first carbapenem released for clinical use was imipenem (5.46), a compound with relatively high resistance to microbial /3-lactamases. The addition of the (iminomethyl)amino side chain renders imipenem chemically more stable than thienamycin. But, like thienamycin, imipenem is also easily hydrolyzed by renal dehydropeptidase I, producing a mixture of /3-lactam ring-opened 1-pyrrolidine epimers at C(3) [161], The renal metabolism of imipenem can be minimized by co-administration of cilastatin (5.53), a competitive inhibitor of DHP-I [15 6] [162],... 

Extensive carbapenem and penem antibiotic research has been ongoing since thienamycin was discovered in 1978. However, only the imipenem-cilastatin combination has become a commercial product. Launched in 1985 in the United States as a broad-spectmm hospital product under the name Ptimaxin, this product had worldwide sales of some 300 million in 1988. Sales were predicted to rise to 345 million for the year ending 1989 (154). 

The 1-caibapenems (Fig. 5.5C) comprise a new family of fused /3-lactam antibiotics. They are analogues of penicillins or clavams, the snlphur (penicilhns) or o gen (calvams) atom being replaced by carbon. Examples are the olivanic acids (section 2.5.1) and thienamycin and imipenem (section 2.5.2). 

Thienamycin (Fig. 5.5E) is a broad-spectrum /3-lactam antibiotic with high /3-lactamase resistance. Unfortunately, it is chemically unstable, although the TV-formimidoyl derivative, imipenem, overcomes this defect. Imipenem (Fig. 5.5E) is stable to most/3-lactamases but it readily hydrolysed by kidney dehydropeptidase and is administered with a dehydropeptidase inhibitor, cilastatin. Meropenem, which has yet to be marketed, is more stable than imipenem to this enzyme and may thus be administered without cilastatin. Its chemical structure is depicted in Fig. 5.5F. 

Imipenem (5.46) has not completely fulfilled such expectations [122], Indeed, this compound is unstable in both acidic and alkaline media. In weakly acidic solutions, imipenem undergoes complex oligomerization, a reaction initiated by the intermolecular attack of the carboxy group on the /3-lactam Fig. 5.17) and yields, finally, a diketopiperazine compound. In weakly alkaline solution, an intermolecular reaction between the /3-lactam and (iminome-thyl)amino group was observed Fig. 5.18). This reaction proceeds via an unstable dimer that breaks down to thienamycin (5.45) and a /3-lactam ring-opened compound bearing a Ai-formyl group [123],... 

Fig. 5.18. Base-catalyzed decomposition of imipenem (5.46) initiated by an intermolecular reaction between the ji-lactam and (iminomethyl)amino group. The reaction generates one molecule of thienamycin (5.45) [123].

Both of these antibiotics are notable. Imipenem is derived from a natural product, thienamycin. 

Imipenem Imipenem, [5R-[5a,6a(R)]]-6-(l-hydroxyethyl)-3-[[2-[(iminomethyl)amino] ethyl]thio]-7-oxo-l-azabicyclo[3.2.0]hept-2-en-2-carboxyUc acid (32.1.3.1), is the only car-bapenem presently used in clinics. It is synthesized from thienamycin isolated from Streptomyces cattleya by reacting it with the methyl formimidate [179-182]. 

Pharmacology This product is a formulation of imipenem, a thienamycin antibiotic, and cilastatin sodium, the inhibitor of the renal dipeptidase, dehydropeptidase-1, which is responsible for the extensive metabolism of imipenem when it is administered alone. Cilastatin prevents the metabolism of imipenem, increasing urinary recovery and decreasing possible renal toxicity. The bactericidal activity of imipenem results from the inhibition of cell-wall synthesis, related to binding to penicillin-binding proteins (PBP). 

Thienamycin and its derivatives are exciting new antibiotics. Then-clinical use is limited, however, by their susceptibility to the kidney enzyme dehydropeptidase I. Reversible inhibition of this enzyme is provided by cilastatin [11]. The preparation of the S-cyclopropane portion [10] of cilastatin is achieved (16) by decomposition of ethyl diazoacetate in isobutylene [9] in the presence of the chiral copper catalyst R-7644. The product [10] is obtained in 92% e.e. and then further processed to cilastatin. Cilastatin is now marketed in combination with the thienamycin derivative imipenem as a very-broad-spectnim antibiotic. 

Tune BM., Fravert D, Hsu C-Y. Thienamycin nephrotoxicity. Mitochondrial injury and oxidative effects of imipenem in the rabbit kidney. Biochem Pharmacol 1989 38(21) 3779-3783. 

The search continues for the ideal beta-lactam antibiotic, and numerous esoteric substances have been isolated from natural sources or have been synthesised during the past 15 years. These include the penems, carbapen-ems, cephamycins, monobactams, etc. The penems are wholly synthetic and from a clinical viewpoint have not been successful, while more success has been obtained with the carbapenems, which include the natural product thienamycin (from Streptomyces cattleya) and the analogues imipenem and meropenem. These carbapenems have a remarkable spectrum of antibacterial activity with a very high activity against pseudomonads. Thienamycin is relatively unstable, but the addition of a formamidine group to produce... 

Verpooten GA, Verbist L, Buntinx AP, Entwistle LA, Jones KEI, De Broe ME. The pharmacokinetics of imipenem (thienamycin-formamidin) and the renal dehydropeptidase inhibitor cilastatin sodium in normal subjects and patients with renal failure. Brit J Clin Pharmacol 1984 18 193-193. 

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