Design, synthesis, biological evaluations and in silico studies of N-substituted 2,4-thiazolidinedione derivatives as potential a-glucosidase inhibitors.

Diabetes mellitus is considered as one of the principal global health urgencies of the twenty first century. In the present investigation, novel N-substituted 2,4-thiazolidinedione derivatives were designed, synthesized, and characterized by spectral techniques. All the newly synthesized N-substituted 2,4-thiazolidinedione derivatives were tested for in vitro α-glucosidase inhibitory activities and compounds A-12 and A-14 were found to be the most potent which were further subjected to in-vivo disaccharide loading test. The most potent compound was also found to be non-toxic in cytotoxicity studies. Further, docking studies were carried out to investigate the binding mode and key interactions with amino acid residues of α-glucosidase. Molecular dynamic simulations studies for the compounds acarbose, A2, A12, and A14 were done with α-glucosidase protein. Further, ΔG was calculated for acarbose, A2, A12, and A14. In silico studies and absorption, distribution, metabolism, excretion (ADME) prediction studies were also executed to establish the 'druggable' pharmacokinetic profiles. Here, we have developed novel N-substituted TZD analogues with different alkyl groups as α-glucosidase inhibitors.Communicated by Ramaswamy H. Sarma.

Preclinical Investigation of Transdermal Route for Enhanced Bio-performance of Duloxetine HCl.

The aim of the study was to develop and optimise drug-in-adhesive (DIA) transdermal patch of duloxetine HCl for enhanced drug delivery. DIA patch so developed reduced the dose and dosing frequency by enhancing bio-performance of the drug. A transdermal DIA patch having Duro-Tak 87-2287 as DIA polymer and Transcutol P as permeation enhancer loaded with 40% drug previously complexed with MeßCD duly characterised (FTIR, DSC, and SEM) was developed for in vivo study. Pharmacokinetic parameters of developed formulation were assessed and compared with oral route of administration. Among various permeation enhancers (PEs), Transcutol P exhibited most enhanced permeation (ER ≈ 1.99) in terms of flux and Q24 compared to control group having. Mean of maximum plasma concentration (Cmax) and area under time-concentration curve (AUC0-72) in Wistar rats (n = 6) for transdermal patch (10 mg/kg) was found to be 70.31 ± 11.2 ng/ml and 2997.29 ± 387.4 ng/ml*h, respectively, and were considerably higher than oral dose of DLX (20 mg/kg and 10 mg/kg). Albeit, T1/2 was higher in case of transdermal delivery, but this was due to sustained behaviour of delivery system. These findings highlight the significance of both inclusion complexation and transdermal delivery of DLX using DIA patch for efficient drug absorption.

Transdermal delivery of duloxetine-sulfobutylether-ß-cyclodextrin complex for effective management of depression.

Aim of the study was to reduce the dose and dosing frequency of duloxetine HCl (DXT) by complexation with sulfobutylether-ß-cyclodextrin (SBEßCD), an anionic cyclodextrin through permeation enhancement for more effective management of depression. Spray dried inclusion complexes of drug with SBEßCD were prepared and incorporated in medicated patches followed by their ex vivo permeation and skin retention studies. Then, in vivo efficacy and absorption of the drug from developed optimised patch was determined in Wistar rats by administering drug through oral route (free drug) and transdermal route (complexed drug). Swimming, immobility and climbing parameters in FST while ambulation and rearings parameters in LAT test were assessed. Addition of permeation enhancer (PE) increased drug permeation and the enhancement ratio (ER) was 3.05 and 1.67 for the patch having complexed DXT and spray dried sample of DXT in comparison to free DXT respectively. The amount of drug retained in skin and in optimized medicated patch after 72 h was relatively lower compared to the formulation having free DXT. Enhanced antidepressive activity was observed for complexed drug compared to free drug. We believe that spray dried complexation based transdermal patch can serve as potential innovative drug delivery system for DXT.

Impact of cyclodextrin derivatives on systemic release of duloxetine HCl via buccal route.

Aim: The aim of this work was to develop buccoadhesive tablets for the systemic delivery of duloxetine HCl (DXT) using more soluble derivatives of ß-cyclodextrin, i.e. hydroxypropyl-ß-cyclodextrin (HPßCD) and sulfobutylether-ß-cyclodextrin (SBEßCD) and to investigate enhanced cellular uptake of inclusion complexed drug.Materials and methods: Freeze dried and spray dried complexes of both cyclodextrin derivatives with DXT (1:1 molar) were prepared and characterized with DSC, FTIR, and PXRD techniques. C971 and PC, on the basis of swelling behavior, erosion and in vitro residence time, were selected for further study at different levels (-1, 0, +1) to optimize the formulation in terms of enhanced drug release and ex vivo permeation.Results: SBEßCD based complexes show more aqueous solubility of DXT (0.782 and 0.958 mM) and more complexation efficiency compared to HPßCD at 25 °C and 37 °C, respectively. Apparent stability constant was reported to be higher (1109.94 and 1693.25 M-1) for DXT-SBEßCD at 25 °C and 37 °C, respectively, than the corresponding values for DXT-HPßCD systems. Enhanced cellular uptake using fibroblast cells was revealed for complexed drug compared to free drug .Conclusion: Both cyclodextrin derivatives are able to enhance drug release and permeation in vitro and ex vivo.

GLP-1 Receptor Agonists in Type 2 Diabetes Mellitus.

The rising epidemic of type 2 diabetes mellitus & associated complications is a serious cause of concern for humanity. Glucagon-like peptide-1 receptor agonists commonly abbreviated as GLP-1 RAs, emerged as a promising therapeutic class based on incretin therapy that regulates glucose metabolism through multiple mechanisms. In the present study, various investigational & clinically used GLP-1 RAs have been reviewed with emphasis on their efficacy, structural modifications, adverse effects and toxicities. Various clinical trials justifying their efficacy have also been included, which highlighted the potential of GLP-1 RAs over conventional anti hyperglycaemic agents through a study of pooled effect on glycemic efficacy and weight-loss. The significant potency and appreciable safety of GLP-1 RAs manifested their potential as a logical approach for the management of type 2 diabetes.

Therapeutic potential of oxazole scaffold: a patent review (2006-2017).

INTRODUCTION: Oxazoles are oxygen and nitrogen containing five membered heterocyclic ring systems that are present in various anticancer, antimicrobial, antihyperglycemic, anti-inflammatory agents etc. of natural origin. These pharmacologically active oxazole derivatives have attracted numerous researchers to explore this scaffold for the design and development of newer potential therapeutic agents. A large number of synthetic oxazole containing molecules have been reported over the period that exhibited wide spectrum of pharmacological profiles. Some of them have shown promising therapeutic potential and have qualified for both preclinical and clinical evaluations. AREAS COVERED: In this review, the patents (published during 2006-2017) focusing on the biological potential of oxazoles have been covered. Therapeutic applications and various techniques/assays employed for the in vitro/in vivo evaluation of patented derivatives have been discussed majorly. EXPERT OPINION: Chemically oxazole offers three positions for substitution. These substituted oxazole derivatives of natural as well as synthetic origin have numerous pharmacological applications including anticancer, anti-Alzheimer's, anti-hyperglycemic, anti-inflammatory, antibacterial etc. Their pharmacological actions are mainly mediated through enzyme/receptor involved in the particular disease. The flexible nature of this ligand for various molecular level targets (enzyme/receptor) make this heterocylce an attractive scaffold for development of effective and clinically relevant oxazole containing therapeutic agents.

Fructose-1,6-bisphosphatase inhibitors: A new valid approach for management of type 2 diabetes mellitus.

The rising incidence of diabetes and confines allied with clinical therapies emphasized the need to explore new molecular targets to develop novel, effective and safer antihyperglycemic agents. Excessive endogenous glucose production by gluconeogenesis is a primary determinant of hyperglycemia in patients with type 2 diabetes. But not even a single current medication acts directly to reduce gluconeogenesis. Fructose-1,6-bisphosphatase (FBPase), a well recognized rate controlling enzyme of gluconeogenesis, has emerged as legitimate molecular level target to control gluconeogenesis mediated glucose overproduction and its inhibitors are likely to fulfill an unmet medical need. In this compilation various chemical classes of FBPase inhibitors have been reviewed which mainly acts through uncompetitive and non-competitive manner. A detailed account on structure activity relationship studies of inhibitors have been presented along with their molecular level interactions at binding sites of enzyme. Three Dimensional Quantitative Structure Activity relationship (3D-QSAR) studies, performed to optimize the lead, have been summarized at some places. In this assemblage, FBPase inhibitors patented in past have been compiled in tabular form. This review highlights the new insight into the therapeutic utility of FBPase inhibitors and their potential as a new class of antidiabetic drugs.

Validation of TZD Scaffold as Potential ARIs: Pharmacophore Modeling, Atom-based 3D QSAR and Docking Studies.

OBJECTIVE: Metabolic disorders associated with diabetic patients are a serious concern. Aldose reductase (ALR2) has been identified as first rate-limiting enzyme in the polyol pathway which catalyzes the reduction of glucose to sorbitol. It represents one of the validated targets to develop potential new chemical entities for the prevention and subsequent progression of microvascular diabetic complications. In order to further understand the intricate structural prerequisites of molecules to act as ALR2 inhibitors, ligand-based pharmacophore model, atombased 3D-QSAR and structure based drug design studies have been performed on a series of 2,4- thiazolidinedione derivatives with ALR2 inhibitory activity. METHODS: In the present study, a validated six point pharmacophore model (AAADNR) with three hydrogen bond acceptor (A), one hydrogen bond donor (D), one negative ionic group (N) and one aromatic ring (R) was developed using PHASE module of Schrodinger suite with acceptable PLS statistics (survival score = 3.871, cross-validated correlation coefficient Q2 = 0.6902, correlation coefficient of multiple determination r2 = 0.9019, Pearson-R coefficient = 0.8354 and F distribution = 196.2). In silico predictive studies (pharmacophore modeling, atom-based 3D QSAR and docking combined with drug receptor binding free energetics and pharmacokinetic drug profile) highlighted some of the important structural features of thiazolidinedione analogs required for potential ALR2 inhibitory activity. RESULTS: The result of these studies may account to design a legitimate template for rational drug design of novel, potent and promising ALR2 inhibitors.