Current Drug Discovery Technologies (v.11, #2)

Nicotinic Acid and its Derivatives: Synthetic Routes, Crystal Forms and Polymorphs by Pan-Pan Zhou, Xiao-Bo Sun, Wen-Yuan Qiu (97-108).
Nicotinic acid is a well-known pharmaceutical in the vitamin B group that has attracted great interest in the pastdecades due to its significant importance in the treatment of the human diseases like pellagra. Also, nicotinic acid derivativeshave been devoted to much attention due to their different pharmaceutical effects in the treatment of diseases. Inview of this, the developments of nicotinic acid and its derivatives including their synthetic methods by using differentsubstrates, and their structural modifications (e.g., substitution of one or more positions of pyridyl ring or acid) were reviewedin details. Drug molecules like nicotinic acid and its derivatives may exist in more than one crystal form in itssolid state, known as polymorphs. Different polymorphs have different dissolution rates and aqueous solubility. Therefore,we reviewed structures of different crystal forms of nicotinic acid and its derivatives.

The pharmaceutical industry is experiencing comeback sales growth due in large part to the industry's R&D effortsthat center on biologics drug development. To facilitate that effort, tools are being developed for more effective biologicdrug development. At the forefront of this effort is epitope characterization, in particular epitope binning, primarilydue to the role an epitope plays in drug function. Here we detail the financial advantages of epitope binning including (1)increased R&D productivity due to increased work in process, (2) reduced number of “dead-end”candidates, and (3) increasedabilityto reengineer antibodies based on the epitope. With the arrival of high throughput biosensors, this manuscriptserves as a call to push epitope binning earlier in the biological drug discovery process.

Potent Phosphatidylinositol 3-Kinase Inhibitors and Their Biology by Mukesh Chandra Joshi, Krishan Kumar, Vikrant Kumar (113-126).
The Phosphoinositide 3-kinase (PI3k) is an important regulator of intracellular signalling pathways, like cellproliferation, migration, survival, and angiogenesis upon activation by growth factor or receptors. The PI3k's pathway isfrequently up-regulated in human cancers, thus inhibition of PI3k's is a promising approach for cancer therapy. Many potentPI3k's inhibitors have been reported so far and few of them are in clinical trial like GDC-0941, BGT-226, AZD-6482and others are natural products etc.

Selective Cyclooxygenase Inhibitors: Current Status by Ravindran Nandakishore, Prasanna R. Yalavarthi, Yengala R. Kiran, Malepati Rajapranathi (127-132).
For ages aspirin has established its value as an analgesic, anti-inflammatory drug, but in 1938, it was found tobe a causative factor of gastric inflammation (ulcer). Later discovered non-steroidal anti-inflammatory drugs (NSAIDs)were found effective as aspirin but failed to overcome the goal of safer aspirin. As the method of prostaglandin inhibitionthrough COX is a common mechanism to both the wanted and unwanted effects of aspirin and non-aspirin NSAIDs, theCOX enzyme becomes a target for drug designers for the development of the “safe aspirin”. In the late 1990s, a new classof drug molecules collectively known as selective inhibitors of cyclooxygenase-2(Coxibs) was developed for the treatmentof pain and inflammation. Coxibs developed were as efficacious as the common NSAIDs, but they are devoid of majorside effect, the gastrointestinal bleeding. This review presents an overview on all the discovered COX-2 inhibitors,their physiological role, side effects and reasons of their withdrawal.

Design and Synthesis of New Potent Inhibitors of Farnesyl Pyrophosphate Synthase by Volodymyr Prokopenko, Vasyl Kovalishyn, Michael Shevchuk, Iryna Kopernyk, Larysa Metelytsia, Vadim Romanenko, Sergey Mogilevich, Valery Kukhar (133-144).
Predictive QSAR models for the inhibition activities of nitrogen-containing bisphosphonates (N-BPs) againstfarnesyl pyrophosphate synthase (FPPS) from Leishmania major (LeFPPS) were developed using a data set of 97 compounds.The QSAR models were developed through the use of Artificial Neural Networks and Random Forest learningprocedures. The predictive ability of the models was tested by means of leave-one-out cross-validation; Q2values rangingfrom 0.45-0.79 were obtained for the regression models. The consensus prediction for the external evaluation set affordedhigh predictive power (Q2=0.76 for 35 compounds).;The robustness of the QSAR models was also evaluated using a Y-randomization procedure. A small set of 6 new N-BPswere designed and synthesized applying the Michael reaction of tetrakis (trimethylsilyl) ethenylidene bisphosphonate withamines. The inhibition activities of these compounds against LeFPPS were predicted by the developed QSAR models andwere found to correlate with their fungistatic activities against Candida albicans. The antifungal activities of N-BPs bearingn-butyl and cyclopropyl side chains exceeded the activities of Fluconazole, a triazole-containing antifungal drug. Inconclusion, the N-BPs developed here present promising candidate drugs for the treatment of fungal diseases.

Chronic myeloid leukaemia (CML) is a disease induced by the BCR-ABL oncogene. Tyrosine kinase inhibitors(TKIs) were introduced in the late 1990s and have revolutionized the management of CML. The majority of such patientscan now expect to live a normal life providing they continue to comply with TKI treatment. However, in a significantproportion of cases, TKI resistance develops over time, requiring a change of therapy. Over the past few years, multiplemolecular mechanisms of resistance have been identified and some common themes have emerged. One is the developmentof resistance mutations in the drug target that prevent the drug from effectively inhibiting the respective TK domain.The second is activation of alternative molecules that maintain the signalling of key downstream pathways despitesustained inhibition of the original drug target.;In this mini-review, we summarize the concepts underlying resistance, the specific examples known to date and the challengesof applying this knowledge to develop improved therapeutic strategies to prevent or overcome resistance.

Racecadotril is an antisecretory and antidiarrheal agent against watery diarrhoea in children. Racecadotril is aclass II drug (as per Biopharmaceutical Classification System) with poor aqueous solubility and dissolution rate limitedabsorption. β-cyclodextrin complexation of solubility or dissolution rate limited drugs provides an amphiphilic complexwith improved solubility and dissolution profile. Thus Racecadotril - β-cyclodextrin complex were prepared to improveits solubility and dissolution by imparting an environment of improved hydrophilicity.;Racecadotril was complexed with β-cyclodextrin (in 1:1 and 1:2 molar ratios) by two different methods (solvent evaporationand kneading method). These inclusion complexes were evaluated for solubility, drug content, scanning electron microscopy(SEM), differential scanning calorimetry (DSC), X ray powder diffraction (XRPD) and in vitro dissolutionstudy.;The highest drug content (30.83%) was found in complex made by kneading method (RK1:1) in 1:1 molar ratio. Complexprepared by solvent evaporation method (RSE1:1, RSE1:2) were found to be showing irregular disc shaped non-poroussurface, while the complexes prepared by kneading method (RK1:1, RK1:2) showed rough, fluffy, non-porous and irregularsurface in SEM. Solubility of the drug improved up to 2 to 3 folds in the complexes. The complex RK1:1 showed thegreatest improvement in solubility (from 28.98 to76.56 µg/ml). The dissolution of the complexes was also found to be improved.Complex prepared by solvent evaporation method in 1:1 molar ratio (RSE1:1) showed a marked improvement inpercent drug release (100.33%) than that of pure drug (52.58%) at the end of 1 hour in dissolution study. FTIR, DSC andXRPD data confirmed the formation of inclusion complex. It was concluded that water solubility of all the complexeswere increased when the drug was complexed with β-CD in 1:1 molar ratio. The complex made in 1:1 molar ratio(irrespective of the method) showed better solubility and the dissolution profile as compared to the complex made in 1:2molar ratio. It was concluded that the complex prepared by the solvent evaporation method showed better solubility andthe dissolution due to better amorphization of the drug.

In-Vitro Assessment and Pharmacodynamics of Nimesulide Incorporated Aloe vera Transemulgel by KR Vandana, Prasanna R. Yalavarthi, CR Sundaresan, Raghava N. Sriramaneni, Harini C. Vadlamudi (162-167).
The aim of the investigation was to prepare nimesulide emulsion for incorporation in Aloe vera gel base toformulate 'nimesulide - Aloe vera transemulgel' (NAE) and to carryout in-vitro assessment and in-vivo anti-inflammatorystudies of the product. Although the use of nimesulide is banned for oral administration, due to its potential for inducinghepatotoxicity and thrombocytopenia, the use of nimesulide for topical delivery is prominent in the treatment of many inflammatoryconditions including rheumatoid arthritis. The drug loading capacity of transdermal gels is low for hydrophobicdrugs such as nimesulide. Nimesulide can be effectively incorporated into emulgels (a combination of emulsion andgel). Aloe vera has a mild anti-inflammatory effect and in the present study Aloe vera gel was formulated and used as agel base to prepare NAE. The emulgels thus prepared were evaluated for viscosity, pH, in-vitro permeation, stability andskin irritation test. In-vivo anti-inflammatory studies were performed using carrageenan induced hind paw edema methodin Wistar rats. The results were compared with that of commercial nimesulide gel (CNG). From the in-vitro studies, effectivepermeation of nimesulide from NAE (53.04 %) was observed compared to CNG (44.72 %) at 30 min indicating betterdrug release from NAE. Topical application of the emulgel found no skin irritation. Stability studies proved the integrityof the formulation. The percentage of inhibition of edema was highest for the prepared NAE (67.4 % inhibition after 240min) compared to CNG (59.6 %). From our results, it was concluded that the Aloe vera gel acts as an effective gel base toprepare nimesulide emulgel with high drug loading capacity (86.4 % drug content) compared to CNG (70.5 % drug content)with significant anti-inflammatory effect.