KY-109, a new bifunctional pro-drug of a cephalosporin. Chemistry, physico-chemical and biological properties.

Abstract

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.(KY-087)1) is a cephalosporin with a broad spectrum of antibacterial activity in vitro. It is, however, poorly absorbed from the gastro-intestinal tract after oral administration, probably due to its low lipo-philicity. An ester pro-drug approach is frequently utilized as a method for increasing the lipophilicity of a drug and thereby improving its absorption after oral administration. A j5-lactam antibiotic containing a relatively basic amino group can give an ester with high lipophilicity and sufficient aqueous solubility, which is significantly better absorbed orally than the parent drug1). Examples of such successful compounds are the pivaloyloxymethyl3), 1-ethoxycarbonyloxyethyl4), phtalidyl5) and (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl6) esters of ampicillin. In contrast, esters of 3-lactam antibiotics lacking a basic amino group in the side chain, such as KY-087, generally seem to be weakly active when given orally, probably because they lack sufficient solubility in water for efficient absorption from the gastro-intestinal tract to occur2,7). To overcome the low aqueous solubility of such esters of KY-087, we have prepared (5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-3-cephem-4-carboxylate hydrochloride, having in addition to the ester group in the 4-position an L-alanine ester formed with the side chain a-hydroxyl group. Due to the amino group in the alanine residue, the bifunctional pro-drug might be expected to have increased aqueous solubility along with a lipophilic character.In this report we describe the physico-chemical and biological properties of the bifunctional prodrug KY-109 in comparison with those of the parent drug (KY-087) and the monofunctional pro-drug (KY-106) having only the ester group in the 4-position.

Cefcanel Daloxate versus Penicillin in Acute Streptococcal Pharyngotonsillitis

“…Cefcanel daloxate is a cephalosporin prod rug for ora l use (10). It dem on s tra tes improved in vi tro activity agains t Gra m -positive bacteria compared with cepha lexi n .…”