New esters of succinic acid and mixed molecules formed by such esters and a meglitinide analog: Study of their insulinotropic potential

Eighteen novel esters of succinic acid, including three mixed molecules for med of both succinic acid and nateglinide, were examined for their insulino tropic efficiency in isolated rat pancreatic islets. The secretory response to these esters at increasing concentrations of both D-glucose and the est er itself allowed to identify five esters judged of potential interest for further investigations. They include three molecules with CH3-O-CO-CH2-CH2- CO-NH-CH(R)-CO-O- sequence and two mixed molecules with a nateglinide moiet y. The effects of the most potent molecule in the first group and that of t wo of the esters with a nateglinide moiety upon islet biosynthetic activity in vitro and insulin release in vivo, after either oral or intravenous adm inistration were also investigated. The results suggested that mixed molecu les formed of both a succinic acid ester and a meglitinide analog may effic iently stimulate proinsulin biosynthesis and/or insulin release. Further wo rk is required, however, to improve their modality of in vivo administratio n. (C) 2000 Academic Press.