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 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 potential interest for further investigations. They include three molecules with CH(3)-O-CO-CH(2)-CH(2)-CO-NH-CH(R)-CO-O- sequence and two mixed molecules 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 vitro and insulin release in vivo, 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 and/or insulin release. Further work is required, however, to improve their modality of in vivo administration.
Laghmich
A
A
Laboratory of Experimental Medicine, Brussels Free University, 808 Route de Lennik, Brussels, B-1070, Belgium.
Ladrière
L
L
Dannacher
H
H
Björkling
F
F
Malaisse
W J
WJ
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D005260:Female; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D011384:Proinsulin / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D013386:Succinates / Q000494:pharmacology*
D001549:Benzamides; D007004:Hypoglycemic Agents; D013386:Succinates; C030516:meglitinide; D011384:Proinsulin