KY-109, A NEW BIFUNCTIONAL PRO-DRUG OF A CEPHALOSPORIN: CHEMISTRY, PHYSICO-CHEMICAL AND BIOLOGICAL PROPERTIES

(5-Methyl-2-oxo-1, 3-dioxol-4-yl)methyl 7-[D-O-(L-alanyl)mandelamido]-3-[[(5-methyl-1, 3, 4-thiadiazol-2-yl)thio]methyl]-3-cephem-4-carboxylate hydrochloride (KY-109) was synthesized as a bifunctional pro-drug designed to improve the oral absorption of the parent drug (KY-087), a cephalosporin similar in activity to cefamandole. The pro-drug was found to possess the desired factors for an orally active pro-drug, that is, appropriate solubility, lipophilicity and ease hydrolysis into the parent drug. As predicted from these factors, the pro-drug when administered orally to rats was well absorbed, and gave high blood levels of the parent drug.