Tsuyoshi Takasaki

Syntheses and Pharmacokinetic Studies of Prodrug Esters for the Development of Oral Carbapenem, L-084

We discovered an orally active carbapenem, L-084, through pharmacokinetic studies on various prodrug esters of (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[1-(1,3-thiazolin-2-yl)azetidin-3-yl]thio-1-carbapen-2-em-3-carboxylic acid (LJC11,036). L-084 showed a strong antimicrobial activity against Gram-positive and Gram-negative bacteria and exhibited the highest intestinal absorption among synthesized prodrugs of LJC11,036.

On the Absolute Configuration in 1,4-Dihydrothiazepine Covalent Complexes Derived from Inhibition of Class A and C β-Lactamases with 6-Methylidene Penems

Serine and metallo b-lactamases catalyze the hydrolysis of blactam rings in all classes of blactam antibiotics which is a major cause of bacterial resistance to b-lactam antibiotics. Bacterial resistance is addressed clinically by combining a b-lactamase inhibitor, such as clavulanic acid, sulbactam, or tazobactam, with a b-lactam antibiotic (amoxicillin or piperacilin). Whereas this strategy is effective with the class A b-lactamase inhibitors, there is an urgent need to extend the spectrum of activity to the other classes of serine b-lactamases including the class C enzymes. Recently, new promising inhibitors of class C b-lactamases such as NXL104, AVE1330A, and diaroylphosphates have been disclosed. Reports from our laboratories on 6-methylidene penems as mechanism-based inhibitors of serine-reactive class A and C b-lactamases disclosed extensive structure–activity relationships with penems containing monocyclic, [6,5]-bicyclic,and [5,5,5]-tricyclic heterocycles that adopt the Z configuration at the C6 position. The mode of action of penem inhibitors involves acylation by the catalytic serine residues followed by b-lactam ring opening and a sequence of transformations amounting to a remarkable 7-endo trig rearrangement reaction. Penems 1–3 have been studied by a plethora of methods to establish the formation of the 1,4-dihydrothiazepine acyl–enzyme complex (Figure 1). The complex is stable to hydrolysis because of the displacement of water molecules. However, an issue concerns the absolute stereochemistry of the C7 moiety bearing the heterocyles. In dihydrothiazepine 4 bearing the methyltriazolyl heterocyle, the S-stereochemistry is evidenced by kinetic, computational, and X-ray crystallographic studies in class A and C enzymes. The dihydroimidazo ACHTUNGTRENNUNG[2,1-c]oxazine thiazepine 5 exists as the R-isomer in the crystal structure of both SHV-1 and GC1 enzymes. A novel hydrophobic p-p stacking interaction between the C7 heterocycle with Tyr105 in SHV-1 and Tyr224 in GC1 was revealed. Furthermore, calculated interaction energy differences between C7R and C7S isomers of eight 6-methylidene penems bearing [6,5]-fused bicyclic heterocycles favor the formation of the C7R over the C7S enantio-

Targeting Val 216 in Class A β-Lactamases with Tricyclic 6-Methylidene Penems

Recently, we reported on the discovery and biological activities of tricyclic 6-methylidene penems as mechanism-based inhibitors of serine b-lactamases. In combination with piperacilin, these inhibitors proved to be highly potent in inhibiting the hydrolysis of b-lactam rings, which is a major cause of bacterial resistance to b-lactam antibiotics. Earlier efforts focused on [5,5,5]-tricyclic penems, such as compound 1, which rearranges