ABSTRACT
SGLT2 has become a target of therapeutic interest in diabetes research. CoMFA and CoMSIA studies were performed on C-aryl glucoside SGLT2 inhibitors (180 analogues) as potential anti-diabetic agents. Three different alignment strategies were used for the compounds. The best CoMFA and CoMSIA models were obtained by means of Distill rigid body alignment of training and test sets, and found statistically significant with cross-validated coefficients (q²) of 0.602 and 0.618, respectively, and conventional coefficients (r²) of 0.905 and 0.902, respectively. Both models were validated by a test set of 36 compounds giving satisfactory predicted correlation coefficients (r² pred) of 0.622 and 0.584 for CoMFA and CoMSIA models, respectively. A comparison was made with earlier 3D QSAR study on SGLT2 inhibitors, which shows that our 3D QSAR models are better than earlier models to predict good inhibitory activity. CoMFA and CoMSIA models generated in this work can provide useful information to design new compounds and helped in prediction of activity prior to synthesis.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Glucosides/chemistry , Glucosides/pharmacology , Hypoglycemic Agents/pharmacology , Sodium-Glucose Transporter 2 Inhibitors , Molecular Structure , Quantitative Structure-Activity RelationshipABSTRACT
HIstamine is a biomolecular compound located in various parts of body. It participated in various important cellular activities associated with allergy and asthma. This magic bio-molecule is directly and indirectly involved in various biochemical reactions through G-protein couple receptors. Various histamine receptors and their unexplored biochemical activities attracted many biologists in last few decades. A surprising discovery of histamine H(4) receptor was done when scientist worked on histamine H(3) receptor in brain cells. The binding pocket of histamine H(4) differs by transmembrane domains (TM3, TM5 and TM6) from histamine H(3)-sub type. In this review, we enlightened various functions of histamine H(4) and use of histamine H(4) receptor antagonists in autoimmune diseases, allergic responses, inflammatory responses, and in superoxide generation which are helpful to establish H(4) receptor antagonists as newer anti histamines.
Subject(s)
Hypersensitivity/immunology , Hypersensitivity/therapy , Receptors, G-Protein-Coupled/immunology , Receptors, Histamine/immunology , Animals , Chemotaxis/drug effects , Humans , Imidazoles/chemistry , Ligands , Receptors, G-Protein-Coupled/chemistry , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Receptors, Histamine/chemistry , Receptors, Histamine/genetics , Receptors, Histamine/metabolism , Receptors, Histamine H4 , Signal TransductionABSTRACT
Present study reports the development and validation of a simultaneous estimation of metformin and gliclazide in human plasma using supercritical fluid chromatography followed by tandem mass spectrometry. Acetonitrile:water (80:20) mixture was used as a mobile phase along with liquid CO(2) in supercritical fluid chromatography and phenformin as an internal standard. The modified plasma samples were analyzed by electro-spray ionization method in selective reaction monitoring mode in tandem mass spectrometry. Supercritical fluid chromatographic separation was performed using nucleosil C(18) containing column as a stationary phase. The separated products were identified by characteristic peaks and specific fragments peaks in tandem mass spectrometry as m/z 130 to 86 for metformin, m/z 324 to 110 for gliclazide and m/z 206 to 105 for phenformin. The present method was found linear in the concentration ranges of 6.0-3550 ng/ml and 7.5-7500 ng/ml for metformin and gliclazide, respectively. Pharmacokinetic study was performed after an oral administration of dispersible tablets containing 500 mg of metformin and 80 mg of gliclazide using same techniques.
ABSTRACT
To develop the newer pharmaceuticals and to spur the strong growth, being a general property of 'handedness', chirality plays a major role. The Easson-Stedman principle shows the differences in the biological activity between enantiomers resulted from selective reactivity of one enantiomer with its receptor. It helps to improve the pharmacokinetic properties and to remove undesirable side effects by virtue of the unique activity of enantiomers. Racemic switching and marketing drug combinations are used as tools for drug life-cycle management and to redevelop racemic mixtures as single enantiomers.
