Application of regression analysis to the hypoglycemic activities of a series of substituted benzenesulfonamidopyrimidines.
Quantitative structure-activity relationship studies have been performed on two types of sulfonamides with hypoglycemic activity. In the case of the 2-benzenesulfonamidopyrimidines, substituted in the 5 position of the pyrimidine ring a correlation between hydrophobic forces, expressed as Rm values, and the binding to serum albumin as well as to the heights of the equipotent dose has been found. In the series of 2-benzenesulfonamidopyrimidines additionally substituted in the 4 position of the benzene ring, however, a correlation between electronic parameters, expressed as the chemical shift of the anilide NH-(type IIA) and benzylamide NH-(type IIb) protons and the biological response was observed. This correlation indicated a charge-controlled second fixation of these molecules to the receptor. This is supported by the observation of stereospecificity of the blood-glucose lowering effect and also by the importance of a constant distance between the nitrogen in the side chain and the nitrogen atom in the sulfonamido group. The correlation between the logarithm of the biological response and the electric effects of the substituents is linear as long as one homologous series is considered. If the anilide and benzylamide derivatives are combined, a linear correlation can only be obtained if a dummy parameter is included which may account for differences in conformation within these two series of compounds.
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D005260:Female; D007004:Hypoglycemic Agents / Q000097:blood / Q000494:pharmacology*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008968:Molecular Conformation; D011485:Protein Binding; D011743:Pyrimidines / Q000097:blood / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D012044:Regression Analysis; D012709:Serum Albumin / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000097:blood / Q000494:pharmacology*
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D011743:Pyrimidines; D012709:Serum Albumin; D013449:Sulfonamides