Conformational analysis of non-sulfonylurea hypoglycemic agents of the meglitinide family.
Non-sulfonylurea hypoglycemic agents of the meglitinide family such as S3075, repaglinide, KAD-1229, and A-4166, were found to display a comparable U-shaped conformation by molecular modelling, with hydrophobic cycles placed at the extremity of each branch and a peptidic bond placed at the bottom of the U. A comparable conformation was observed with the hypoglycemic sulfonylureas glibenclamide and glimepiride. A different conformation with a greater distance between the hydrophobic cycles at the extremity of each branch was found, however, with the biologically inactive enantiomers of A-4166 and repaglinide and the poorly efficient insulinotropic agent meglitinide. The identification of a common conformation of these hypoglycemic agents may help in the design of highly active compounds and provide an imprint of their postulated target receptor on the pancreatic B-cell plasma membrane.
Lins
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Centre de Biophysique Moléculaire Numérique, Faculté Universitaire de Gembloux, Gembloux, Belgium.
Brasseur
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R
Malaisse
W J
WJ
D001549:Benzamides / Q000737:chemistry*; D002219:Carbamates / Q000737:chemistry; D003510:Cyclohexanes / Q000737:chemistry; D015195:Drug Design; D005905:Glyburide / Q000737:chemistry; D007004:Hypoglycemic Agents / Q000737:chemistry*; D007211:Indoles / Q000737:chemistry; D054833:Isoindoles; D008968:Molecular Conformation; D000077715:Nateglinide; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013453:Sulfonylurea Compounds / Q000737:chemistry*
D001549:Benzamides; D002219:Carbamates; D003510:Cyclohexanes; D007004:Hypoglycemic Agents; D007211:Indoles; D054833:Isoindoles; D010880:Piperidines; C095585:S 3075; D013453:Sulfonylurea Compounds; D000077715:Nateglinide; D010649:Phenylalanine; C072379:repaglinide; C057619:glimepiride; C030516:meglitinide; C087255:mitiglinide; D005905:Glyburide