Design, synthesis, and evaluation of prodrugs of ertapenem.

Carbapenems are intravenous lifesaving hospital antibiotics. Once patients leave the hospital, they are sent home with antibiotics other than carbapenems since they cannot be administered orally due to lack of oral absorption primarily because of very highly polarity. A prodrug approach is a bona fide strategy to improve oral absorption of compounds.

6H-Benzo[c]chromen-6-one derivatives as selective ERbeta agonists.

A series of 6H-benzo[c]chromen-6-one and 6H-benzo[c]chromene derivatives were prepared, and the affinity and selectivity for ERalpha and ERbeta was measured. Many of the analogs were found to be potent and selective ERbeta agonists. Bis hydroxyl at positions 3 and 8 is essential for activity in a HTRF coactivator recruitment assay.

Synthesis and activity of 2-(sulfonamido)methyl-carbapenems: discovery of a novel, anti-MRSA 1,8-naphthosultam pharmacophore.

A series of 1beta-methyl carbapenems substituted at the 2-position with lipophilic, acyclic and cyclic (sulfonamido)methyl groups was prepared and evaluated for activity against resistant gram-positive bacteria. From these studies, the 1,8-naphthosultamyl group emerged as a novel, PBP2a-binding, anti-MRSA pharmacophore worthy of further exploration.

Pharmacokinetics in nonhuman primates of a prototype carbapenem active against methicillin-resistant Staphylococcus aureus.

Pharmacokinetic parameters were determined for imipenem-cilastatin and a carbapenem antibiotic, L-695,256, active against methicillin-resistant Staphylococcus aureus in rhesus monkeys and a chimpanzee. L-695,256 had larger areas under the concentration-time curve than imipenem-cilastatin (30 +/- 5 versus 24 +/- 1 micrograms.h/ml in the rhesus monkeys and 77 versus 60 micrograms.

Structure-activity relationships in the 2-arylcarbapenem series: synthesis of 1-methyl-2-arylcarbapenems.

The labile tert-butyldimethylsilyl esters of the azetidinones 6-8b served as the crucial synthons in the preparation of the potentially useful ylide pyridyl thio esters 18-20. These intermediates were utilized to synthesize a host of title carbapenems 25-30d, 32, and 49-53. The antimicrobial properties and DHP-I susceptibility of these carbapenems were studied with reference to thienamycin.