Ramping glucosuria for management of type 2 diabetes mellitus: an emerging cynosure.

Chronic hyperglycemia is a characteristic feature of type 2 diabetes mellitus (T2DM). The kidney plays a vital role in maintaining blood glucose homeostasis by recovering glucose from glomerular filtrate which is controlled by SGLT2 cotransporters expressed mainly in proximal tubule. In T2DM patients, inhibition of SGLT2 normalizes glycemic levels by preventing glucose from being reabsorbed through SGLT2 and re-entering the circulation. Thus, SGLT2 inhibition seems to be a logical approach and pose a novel insulin-independent mechanism of action for management of T2DM by promoting urinary glucose excretion in the body. Canagliflozin is the first SGLT2 inhibitor approved by US Food and Drug Administration (US FDA) followed by dapagliflozin while empagliflozin is under FDA review. Various other drug candidates in late-stage clinical developments are also expected to hit the global markets in the coming years. In this review, studies on various early- and late-stage SGLT2 inhibitors have been investigated and recent clinical developments summarized.

Advances in the design and discovery of drugs for the treatment of prostatic hyperplasia.

INTRODUCTION: Benign prostatic hyperplasia (BPH) is a common medical problem in nearly 80% of geriatric male population severely affecting the quality of life. Several strategies has been suggested in the past for the management of BPH, but only α-blockers and 5α-reductase inhibitors are in clinical use. This review aims to give deep insight into advances in the design and discovery of newer chemical entities as 'druggable' molecule for the management of BPH. AREAS COVERED: In this review, the authors cover various classes of drugs that have shown their potential for management of BPH. These drugs include α-adrenergic antagonists, 5α-reductase inhibitors, phytochemical agents, phosphodiesterase inhibitor, luteinizing hormone releasing hormone antagonists and muscarinic receptor antagonists. Literature searches were carried out using Google Scholar, SciFinder and PubMed. EXPERT OPINION: The exact etiology of BPH is unknown; however, several mechanisms may be involved in the progression of the disease. Beside surgery and watchful waiting, medical therapies to treat BPH include α-adrenergic antagonist and 5α-reductase inhibitors. Phytotherapeutic agents are also used in some countries. Various other chemical classes of drugs are proposed for the treatment of the disease, but none of them have reached the clinic. Many classes of drugs are currently undergoing clinical trials such as phosphodiesterase inhibitors, luteinizing hormone releasing hormone antagonists and muscarinic receptor antagonists. The current need is to develop a potent, efficacious and highly selective drug for the treatment of BPH.

Validation of formylchromane derivatives as protein tyrosine phosphatase 1B inhibitors by pharmacophore modeling, atom-based 3D-QSAR and docking studies.

Formylchromane derivatives were reported to possess irreversible and selective inhibition on human protein tyrosine phosphatase 1B (PTP 1B). Inhibition of PTP 1B is a molecular level legitimate approach for the management of type 2 diabetes mellitus (T2DM). 3D-QSAR studies were performed on a series of formylchromane derivatives using partial least square (PLS) analysis for correlating molecular architecture of the analogs with their PTP 1B inhibitory activity. A five-point pharmacophore hypothesis with three hydrogen bond acceptors (A) and two aromatic rings (R) as pharmacophoric features was developed using phase module of Schrödinger suite. The hypothesis AAARR.160 was considered as best hypothesis in this study characterized by survival score (3.483), the best cross-validated r² (Q²) (0.774), regression coefficient (0.960), Pearson-R (0.891), and F value (100.3). The results of hypothesis AAARR.160 complimented very closely to interactions witnessed in active site of the ligand-bound complex. The molecular docking simulations into PTP 1B active site also highlighted that biphenyl moiety favorably interacted with amino acid residues lining the lipophilic pocket, and provided hydrophobic interactions with receptor active site. These observations might be useful for further development and optimization of new chemical entities as potential PTP 1B inhibitors prior to its synthesis.

3D-QSAR studies on a series of 2,4-thiazolidinedione derivatives: a self- organizing molecular field analysis approach to design novel PTP 1B inhibitors.

Diabetes mellitus is a group of metabolic disorders characterised by chronic hyperglycemia resulting either from a deficiency of insulin, or decreased ability to transduce the insulin signal, or both. Insulin resistance and ß-cell dysfunction are two fundamental defects known to precede the onset of type 2 diabetes. PTP 1B is considered to function as a negative regulator of insulin signal transduction by dephosphorylating phosphotyrosine residues. 2,4-Thiazolidinediones (TZDs) have long been considered as antihyperglycemic agents which act by ameliorating insulin resistance and thereby normalizing elevated blood glucose level. A three dimensional quantitative structure-activity relationship (3D-QSAR) study was performed on a novel class of thiazolidinedione derivatives using self-organizing molecular field analysis (SOMFA) to correlate their molecular architecture with observed PTP 1B inhibitory activities. The master grid maps derived from the best model were used to display the contribution of both electrostatic and shape potential that can be mapped back onto structural features relating to the trends in inhibitory activities. The present SOMFA study indicated the indispensable molecular features which can be further explored for structural modifications of these lead molecules in order to optimize PTP 1B inhibitory activity.

In silico predicative studies for cytotoxic potential of NSAIDs using self-organizing molecular field analysis.

Antiproliferative potential of nonsteroidal anti-inflammatory drugs (NSAIDs) has generated an immense interest among the scientific fraternity to assess its broader role in the chemoprevention of colon cancer. Due to serious adverse events associated with the chemotherapy, NSAIDs have been exploited as adjuvants to synergize the cytotoxic potential of conventional chemotherapeutic agents at low-dose regimens. The present investigation has been focused on in silico model generation for in vitro cytotoxicity activity of the clinically active NSAIDs using self-organizing molecular field analysis (SOMFA) studies. A statistically validated robust model for a diverse group of NSAIDs having flexibility in structure and cytotoxicity activity was obtained using SOMFA. The statistical measures having good cross-validated correlation coefficient r (2) (cv) (.8291), noncross-validated correlation coefficient r (2) values (.8686), and high F test value (41.8722) proved significance in the generated model. Analysis of 3-dimensional quantitative structure activity relationship (3D-QSAR) models through electrostatic and shape grids provided additional valuable information regarding shape and electrostatic potential influence on in vitro cytotoxicity profile. The analysis of SOMFA results provided a better insight about the generation of molecular architecture of novel NSAIDs yet to be synthesized, with optimum in vitro cytotoxicity activity and improved therapeutic profile.

Saxagliptin: a new drug for the treatment of type 2 diabetes.

Saxagliptin (BMS-477118) has been recently FDA approved drug for the management of T2DM developed by Bristol-Myers Squibb and AstraZeneca under the trade name Onglyza. Saxagliptin is a nitrile-containing selective, potent, reversible and durable DPP IV inhibitor developed as an alternative second-line adds on to Metformin in place of a sulphonylurea. Saxagliptin increases and prolongs the action of incretin hormones by inhibiting the DPP IV enzyme that inactivates incretins usually within minutes. Saxagliptin is well absorbed and has low plasma protein binding and displays slow-binding properties to DPP IV. Saxagliptin is metabolized in vivo to form an active metabolite (BMS-510849), which is twofold less potent than the parent molecule. The X-ray crystallography revealed that Saxagliptin is covalently bound to the DPP IV active site. In drug-native patients with T2DM and inadequate glycemic control, once-daily Saxagliptin monotherapy for 24 wks demonstrated clinically meaningful with no weight gain and generally well tolerated.