Pharmacological Research, Vol. 41, No. 5, 2000 doi:10.1006phrs.1999.0626, available online at http:www.idealibrary.com on NEW ESTERS OF SUCCINIC ACID AND MIXED MOLECULES FORMED BY SUCH ESTERS AND A MEGLITINIDE ANALOG: STUDY OF THEIR INSULINOTROPIC POTENTIAL a ` a b ¨ b A. LAGHMICH , L. LADRIERE , H. DANNACHER , F. BJORKLING and W.J. MALAISSE a, a Laboratory of Experimental Medicine, Brussels Free Uni ersity, 808 Route de Lennik, B-1070 Brussels, Belgium and b Leo Pharmaceutical Products, DK-2750 Ballerup, Denmark Accepted 11 No ember 1999 Eighteen novel esters of succinic acid, including three mixed molecules formed of both succinic acid and nateglinide, were examined for their insulinotropic efficiency in isolated rat pancreatic islets. The secretory response to these esters at increasing concentrations of both D-glucose and the ester itself allowed to identify five esters judged of poten- tial interest for further investigations. They include three molecules with Ž . CH O CO CH CH CO NH CH R CO O sequence and two mixed molecules 3 2 2 with a nateglinide moiety. The effects of the most potent molecule in the first group and that of two of the esters with a nateglinide moiety upon islet biosynthetic activity in itro and insulin release in i o, after either oral or intravenous administration were also investigated. The results suggested that mixed molecules formed of both a succinic acid ester and a meglitinide analog may efficiently stimulate proinsulin biosynthesis andor insulin release. Further work is required, however, to improve their modality of in i o administration. 2000 Academic Press KEY WORDS: rat pancreatic islet biosynthetic and secretory activity, succinic acid esters, nateglinide. INTRODUCTION Hypoglycaemic sulphonylureas and, more recently, meglitinide analogs are the major insulinotropic agents currently used in the treatment of non-in- sulin-dependent diabetes mellitus. In healthy islet B-cells, the secretory response to these agents is modulated by the extracellular concentration of D- glucose 1, 2 . Thus, the increase in insulin output attributable to the drugs is much larger at concen- trations of the hexose close to or in excess of the threshold value for stimulation of insulin release by the sugar itself, than at lower, non-insulinotropic D-glucose concentrations. This modulation may be altered in type 2 diabetes. Indeed, in this disease, the B-cell often displays an apparent ‘blindness’ to D-glucose 3 . It was proposed, therefore, that the concomitant administration of one of these hypogly- caemic agents and a suitable nutrient, able to bypass those site-specific defects in the transport, phospho- Corresponding author. rylation or further metabolism of D-glucose respon- sible for the altered recognition of the hexose by the diseased B-cell, might favour the expression of the insulinotropic potential of the antidiabetic drug. For instance, esters of succinic acid were shown to po- tentiate the secretory response to hypoglycaemic sulphonylureas or meglitinide analogs both in itro and in i o and both in normal and diabetic animals 1, 4 9. In the prolongation of the latter observations, it seemed of interest to investigate whether a mixed molecule formed of both a succinic acid ester and one of the antidiabetic agents may represent a suit- able tool to express their synergistic action upon insulin release. The present study deals with three novel molecules synthesized in such a perspective, as well as several other new esters of succinic acid. MATERIALS AND METHODS Eighteen novel esters of succinic acid were investi- gated. Figures 1 3 depict 15 esters, each of which 104366180005054312$35.000 2000 Academic Press