Wehave studied an ester prodrug of a carbapenem to develop a potent orally active /Mactam antibiotic. A variety of l/?-methylcarbapenem derivatives have been synthesized. We have found that some derivatives having an amide group in the C-2 side chain show potent and well balanced antibacterial activities as well as high stability against dehydropeptidase-I. Oral absorption of derivatives has been optimized by modifying the C-3 ester promoiety. Pivaloyloxymethyl (li?,5S,6S)-6-[(JR)-l-hydroxyethyl]-l-methyl-2-[(jR)-5-oxopyrrolidin-3-ylthio]-l-carbapen-2-em-3-carboxylate, CS-834, has been selected as the most promising compound for further evaluation. An orally active antibiotic with potent activity is of much interest in the clinical realm because oral administration and lower dosage are advantageous for patients. Carbapenems are the most potent jS-lactam antibiotics which have a broad antibacterial spectrum and potent bactericidal activities against both Gram-positive and-negative organisms.1>2) They are highly resistant to hydrolysis by a variety of /Mactamases. So far, imipenem,3) panipenem4) and meropenem5)have been launched on the market, and several compounds are currently under clinical evaluation.6~8) However, most compoundshave been developed for parenteral use, and none for the practical purpose of oral administration. Currently, tricyclic /Mactam antibiotics, GV-1 04326 and its ester GV-118819, have been developed. GV-118819 is now under clinical study as an oral antiinfective drug.9-ll)
Two series of pentacyclic carbazolones, 22 and 23, have been synthesized utilizing a facile intramolecular Dielsminus signAlder reaction and are allosteric modulators at muscarinic acetylcholine receptors. Their affinities and cooperativities with acetylcholine and the antagonist N-methylscopolamine (NMS) at M(1)minus signM(4) receptors have been analyzed and compared. All of the synthesized compounds are negatively cooperative with acetylcholine. In contrast, the majority of the compounds exhibit positive cooperativity with NMS, particularly at M(2) and M(4) receptors. The subtype selectivity, in terms of affinity, was in general M(2) > M(1) > M(4) > M(3). The largest increases in affinity produced by a single substitution of the core structure were given by the 1-OMe (22b) and 1-Cl (22d) derivatives. The position of the N in the ring did not appear to be important for binding affinity or cooperativity. Two compounds 22y and 23i, both trisubstituted analogues, were the most potent compounds synthesized, with dissociation constants of 30minus sign100 nM for the M(2) NMS-liganded and unliganded receptor, respectively. The results indicate that the allosteric site, like the primary binding site, is capable of high-affinity interactions with molecules of relatively low molecular weight.
The degradation kinetics of pivaloyloxymethyl (POM) esters of cephalosporins in phosphate buffer solution (pH 6-8) were investigated. The degradation of the starting delta 3 cephalosporin ester proceeded mainly via isomerization to the delta 2 ester and subsequent hydrolysis to the delta 2 acid. Hydrolysis to the delta 3 acid (the parent acid) was very slow. Analysis of the rate constants indicated that the isomerization rate k12 was approximately equal to the apparent degradation rate of the delta 3 ester kdeg, and slower than the hydrolysis rate of the delta 2 ester k24. The isomerization process to the delta 2 ester was found to be the rate-determining step in the degradation of cephalosporin esters. The substituent at the C-3 position of the cephalosporins affected the degradation kinetics. The degradation was accelerated by increase of pH, buffer concentration and added protein.
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