Viney Lather

Recent Updates on Glucokinase Activators for the Treatment of Type 2 Diabetes Mellitus

Glucose-phosphorylating enzyme, glucokinase (GK) plays a major role in glucose homeostasis primarily through its regulatory actions in pancreatic β-cells and liver hepatocytes. Conversion of glucose to glucose-6-phosphate by GK promotes glycogen synthesis in liver hepatocytes, and insulin release in the pancreatic β-cells. Small molecules called glucokinase activators (GKAs) which bind to an allosteric activator site of the GK enzyme have indeed been discovered and developed, and thus hold great promise as new, effective and safe antidiabetic agents. GKAs enhance the catalytic activity of GK and promising clinical trials in humans demonstrated that they are highly useful in the treatment of type 2 diabetes mellitus. Most of the reported GKAs include amide derivatives like benzamides, acrylamides, carboxamides, acetamides and acrylamides. Examples include Piragliatin, AZD1656, AZD6370, R1440 GKA2, GKA 50, YH GKA, PSN 010, and LY2121260. Recent findings on GKAs including lead compounds and overview of current hypothesis on mechanism of GK activation along with summary of the recently published patents as well as the GKAs of natural origin are reported in the present review.

A Self-nanoemulsifying Drug Delivery System for Poorly Water Soluble Tolbutamide: Development, Optimization and Pharmacodynamic Studies

BACKGROUNDnSelf-nanoemulsifying drug delivery system (SNEDDS) has immense potential in oral bioavailability enhancement of lipophilic drugs.nnnOBJECTIVEnThis investigation involves the development of thermodynamically stable and dilutable SNEDDS for tolbutamide, for achieving higher water solubility and enhanced dissolution rate which in turn improves its oral bioavailability.nnnMETHODnPreliminary solubility studies were carried out and pseudo-ternary phase diagrams were plotted for selection of best ratio of surfactant and co-surfactant. The drug loaded SNEDDS were prepared, characterized w.r.t. refractive index, viscocity, globule size, zeta potential, and TEM, and converted into solid self-nanoemulsifying granules (SSNEGs). These were further characterized and their antidiabetic efficacy in male Wistar rats was evaluated.nnnRESULTSnSolubility studies suggested the suitability of oleic acid as lipid phase; Tween 20 and PEG 400 as optimal surfactant and co-surfactant, respectively for formulation of SNEDDS formulations. The optimal SNEDDS formulation having mean globule diameter, viscosity, polydispersity 58.55 ± 0.2 nm, 26.18 ± 0.2 cps, 0.277 respectively, and infinite dilution capability displayed a highly significant increase in dissolution rate within 5 h compared to pure drug suspension. The SSNEGs showed 1.54 fold increase in drug dissolution rate compared to pure drug. Stability studies revealed no significant change in morphology and globule size. Anti-hyperglycemic activity of tolbutamide loaded SSNEGs in rats showed a significant reduction in elevated blood glucose level with absence of ketone and glucose in urine.nnnCONCLUSIONnThe present study demonstrates a successful development of SNEDDS formulation with an overall potential of bioavailability enhancement for tolbutamide, a BCS-II drug.

Nanocarriers in Drug and Gene Delivery

Nanotechnology has been vastly explored as a delivery carrier for bioactives. Particles in nanorange show entirely different physical and chemical properties. The unique properties of nanoparticles (NPs) owing to their small size and tunable surface properties make them highly attractive for biomedical applications. NPs have made deep inroad as drug delivery carrier and have embraced the future of effective and efficient delivery of pharmaceuticals. As a drug or gene delivery carrier, NPs improve their pharmacokinetic/pharmacodynamic profile and simultaneously reduce the existing toxic effects. The most fascinating feature of NPs is to improve the stability of liable drugs in vitro and in vivo. Several pharmaceuticals especially genetic materials are prone to be degraded in variable physiological conditions before reaching to the target site. Without proper drug delivery vehicle, they can also impart off-target toxicity and lesser therapeutic efficacy. Nanocarriers represent a number of opportunities to deliver bioactives specifically to the target site by using targeting ligands, surface modification, stimuli responsiveness, intracellular trafficking, and sustained release. To date, a number of nanoparticulate systems based on polymers, lipids, proteins, and inorganic materials have been established for delivery application. Since the last two decades, a tremendous progress has been made in the design and development of more efficient nanoplatforms. NPs have revolutionized the area of drug/gene delivery, and rapid growth in the design of novel nanoplatforms holds great promise in disease therapies.

N-Pyridin-2-yl Benzamide Analogues as Allosteric Activators of Glucokinase: Design, Synthesis, In Vitro, In Silico and In Vivo Evaluation

Glucokinase (GK) is the key enzyme controlling levels of blood glucose under normal physiological range, and GK activators are emerging class of drug candidates with promising hypoglycaemic activity. The current study was planned to design, synthesize and evaluate novel N‐pyridin‐2‐yl benzamide analogues as allosteric activators of GK. A novel series of N‐pyridin‐2‐yl benzamide analogues were synthesized starting from 3‐nitrobenzoic acid and evaluated in vitro for GK activation followed by in silico studies to predict the binding interactions of the designed molecules with GK protein. The selected synthesized molecules (compounds 5b, 5c, 5e, 5g, 5h and 6d) which displayed excellent GK activity (GK fold activation around 2) in GK assay and appreciable binding interaction with GK in docking studies were further evaluated for their antihyperglycaemic potential using oral glucose tolerance test (OGTT) in rats. Amongst the compounds tested in vivo (OGTT assay) for antihyperglycaemic potential, compounds 5c, 5e and 5g displayed significant reduction in blood glucose levels. Compound 5e displayed most significant antidiabetic activity and comparable to that of standard drug in animal studies. The N‐pyridin‐2‐yl benzamide analogues discovered in the current study can provide some lead molecules for the development of potent oral GK activators with minimum side‐effects for the management of type 2 diabetes.

Synthesis, Docking and Anti-inflammatory Activity of Some Newer Triazole Derivatives as Potential PDE7 Inhibitors

Phosphodiesterase 7 (PDE7), one of the members of PDE family has been reported as potential therapeutic target involved in inflammation. The present work was designed to synthesize and evaluate the anti-inflammatory activity of some newer substituted triazole derivatives as potential PDE7 inhibitors. A series of substituted triazole derivatives was synthesized and evaluated by in silico studies to determine the binding interactions for the best-fit conformations in the binding site of the PDE7 protein. The selected compounds from in silico studies were evaluated further for their anti-inflammatory activity in the animal models. Amongst the synthesized molecules, compound 3 showed higher anti-inflammatory activity. The in vivo results showed accordance to that of in silico results. Most of the synthesized molecules were found to have drug-like properties as devised by Lipinski’s rule of five. These molecules can act as the starting hits for the design of safe, effective and orally bioavailable PDE7 inhibitors for the treatment of various inflammatory disorders.

Synthesis, Docking and Evaluation of Novel Pyrazole Carboxamide Derivatives as Multifunctional Anti-Alzheimer's Agents

Alzheimer’s disease (AD) is a major public health problem. The dual inhibitors of monoamine oxidase-B (MAO-B) and acetyl cholinesterase (AchE) are reported as effective in treatment of AD. The present research work was planned to design, synthesize and evaluate pyrazole carboxamide derivatives as multifunctional agents for treatment of AD. A series of substituted pyrazole derivatives were synthesized by refluxing chalcone derivatives with substituted semicarbazides and evaluated by in silico docking studies to determine the binding interactions for the best fit conformations in the binding site of MAO-B protein. The selected compounds from the in silico studies were evaluated further for their cognition enhancing and AchE inhibitory activity. Compounds 8 and 11 significantly reversed the scopolamine induced amnesia on elevated plus maze (EPM) model and compound 8 was found to be most potent. The selected compounds also significantly reduced AchE activity in brain. These newly designed molecules could act as starting hits for the development of effective and potent multifunctional agents for the potential treatment of AD.