PubMed · 13636982
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J LEBON, R CLAUDE. 1959. [Hypoglycemic sulfamides].. https://pubmed.ncbi.nlm.nih.gov/13636982/
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The infrared absorption spectrum of antidiabetic drugs Pioglitazone and Pioglitazone.HCl has been recorded at high resolution in the spectral region 200-4000 cm(-1). Most of the frequencies in the latter compound are slightly lower in magnitude than corresponding value in the former. The absorption intensities are however slightly larger. In order to confirm the vibrational assignment of the bands obtained from experimental observation, a normal co-ordinate analysis has been carried out using semi empirical AM1 method through MOPAC 5.1 computer program. In addition to these compounds, the vibrational frequencies for some of the intermediate metabolite of Pioglitazone have also been calculated.
The molecular modelling of oximes having 5-benzyl-2,4-thiazolidinedione moieties, agonists of the peroxisome proliferator-activated receptor gamma (PPAR gamma), was performed with respect to their structures complexed with the ligand binding domain of PPAR gamma. For each ligand molecule, the 5-benzyl-2,4-thiazolidinedione head group was used as an anchor and the conformation of the rest of the molecule was searched for the most energetically favorable interaction with the receptor by systematic conformation search and manual modelling. Although both tail-up and tail-down configurations, which have been observed in the crystal structure of eicosapentaenoic acid when complexed with PPAR delta, appeared among the lowest energy structures for most of the compounds, potent agonists were found to adopt a configuration similar to that of rosiglitazone when bound to PPAR gamma, according to the crystal structure. The structure-activity relationships were analyzed based on the receptor-ligand interaction. The alkyl group and the aromatic ring of the tail group of the ligands had hydrophobic interactions with the receptor, and these interactions were found to be essential for the strong activity.
Analysis of the enantiomers of rosiglitazone in a PPAR gamma binding assay suggests that the (S)-(-)-isomer is responsible for the antidiabetic activity.