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Mumbai, India

Mukherjee K.,Alkem Laboratories Ltd | Chattopadhyay N.,CSIR - Central Electrochemical Research Institute
Biochemical Pharmacology | Year: 2016

Osteoporosis is a metabolic bone disease that is characterized by heightened state of bone resorption accompanied by diminished bone formation, leading to a reduction of bone mineral density (BMD) and deterioration of bone quality, thus increasing the risk of developing fractures. Molecular insight into bone biology identified cathepsin K (CatK) as a novel therapeutic target. CatK is a lysosomal cysteine protease secreted by activated osteoclasts during bone resorption, whose primary substrate is type I collagen, the major component of organic bone matrix. Available anti-resorptive drugs affect osteoclast survival and influence both resorption and formation of bone. CatK inhibitors are distinct from the existing anti-resorptives as they only target the resorption process itself without impairing osteoclast differentiation and do not interfere with bone formation. An inhibitor of CatK, odanacatib, robustly increased both trabecular and cortical BMD in postmenopausal osteoporosis patients. The phase III fracture prevention trial with odanacatib ended early due to good efficacy and a favorable benefit/risk profile, thus, enhancing the opportunity for CatK as a pharmacological target for osteoporosis. So far, all the inhibitors that reached to the stage of clinical trial targeted active site of CatK to abrogate the entire proteolytic activity of the enzyme in addition to the desired blockage of excessive elastin and collagen degradation, and could thus pose safety concerns with long term use. Identification of selective exosite inhibitors that inhibit CatK's elastase and/or collagenase activity but do not affect the hydrolysis of other physiologically relevant substrates of CatK would be an improved strategy to inhibit this enzyme. © 2016.

Boonyasuppayakorn S.,Georgetown University | Boonyasuppayakorn S.,Chulalongkorn University | Reichert E.D.,Georgetown University | Reichert E.D.,Defense Threat Reduction Agency | And 4 more authors.
Antiviral Research | Year: 2014

Dengue virus serotypes 1-4 (DENV1-4) are transmitted by mosquitoes which cause most frequent arboviral infections in the world resulting in ∼390 million cases with ∼25,000 deaths annually. There is no vaccine or antiviral drug currently available for human use. Compounds containing quinoline scaffold were shown to inhibit flavivirus NS2B-NS3 protease (NS2B-NS3pro) with good potencies. In this study, we screened quinoline derivatives, which are known antimalarial drugs for inhibition of DENV2 and West Nile virus (WNV) replication using the corresponding replicon expressing cell-based assays. Amodiaquine (AQ), one of the 4-aminoquinoline drugs, inhibited DENV2 infectivity measured by plaque assays, with EC50 and EC90 values of 1.08 ± 0.09 μM and 2.69 ± 0.47 μM, respectively, and DENV2 RNA replication measured by Renilla luciferase reporter assay, with EC50 value of 7.41 ± 1.09 μM in the replicon expressing cells. Cytotoxic concentration (CC50) in BHK-21 cells was 52.09 ± 4.25 μM. The replication inhibition was confirmed by plaque assay of the extracellular virions as well as by qRT-PCR of the intracellular and extracellular viral RNA levels. AQ was stable for at least 96 h and had minor inhibitory effect on entry, translation, and post-replication stages in the viral life cycle. DENV protease, 5′-methyltransferase, and RNA-dependent RNA polymerase do not seem to be targets of AQ. Both p-hydroxyanilino and diethylaminomethyl moieties are important for AQ to inhibit DENV2 replication and infectivity. Our results support AQ as a promising candidate for anti-flaviviral therapy. © 2014 Elsevier Ltd. All rights reserved.

Thomas S.P.,Indian Institute of Science | Nagarajan K.,Alkem Laboratories Ltd | Row T.N.G.,Indian Institute of Science
Chemical Communications | Year: 2012

Crystal structures of polymorphs and solvatomorphs of the potential anxiolytic drug fenobam exhibit an exclusive preference for one of the two possible tautomeric structures. A novel methodology based on nonlinear optical response has been successfully employed to detect the presence of a polymorphic impurity in a mixture of polymorphs. © 2012 The Royal Society of Chemistry.

Patel D.P.,Gujarat University | Sharma P.,Gujarat University | Patel B.M.,Gujarat University | Sanyal M.,St Xaviers College | And 2 more authors.
Journal of Pharmaceutical and Biomedical Analysis | Year: 2013

A sensitive and rapid ultra performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method has been developed for the determination of 21-hydroxy deflazacort in human plasma using betamethasone as the internal standard (IS). After solid-phase extraction from 100. μL human plasma, the analyte and IS were analyzed on Waters Acquity UPLC BEH C18 (50. mm. ×. 2.1. mm, 1.7. μm) column using acetonitrile-4.0. mM ammonium formate, pH 3.5 (90:10, v/v) as the mobile phase. The protonated analyte was quantified by selected reaction monitoring in the positive ionization mode by triple quadrupole mass spectrometer. The calibration plots were linear over the concentration range 0.50-500. ng/mL. Intra-batch and inter-batch precision (% CV) and accuracy (%) for five quality control samples ranged within 1.40-4.82% and 98.0-102.0% respectively. The overall mean extraction recovery of 21-hydroxy deflazacort from plasma ranged from 95.3 to 97.3%. Matrix effect was assessed by post-column analyte infusion and the extraction recovery was >95.0% across four quality control levels for the analyte and IS. Stability was evaluated under different conditions like bench top, autosampler, processed sample (at room temperature and in cooling chamber), freeze-thaw and long term stability. The method was applied to support a bioequivalence study of 30. mg deflazacort tablet formulation in 28 healthy subjects. Assay reproducibility was demonstrated by reanalysis of 115 incurred samples. © 2013 Elsevier B.V.

Patel D.P.,Gujarat University | Sharma P.,Gujarat University | Sanyal M.,St Xaviers College | Singhal P.,Alkem Laboratories Ltd | Shrivastav P.S.,Gujarat University
Biomedical Chromatography | Year: 2013

An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method has been developed for the simultaneous determination of carvedilol and its pharmacologically active metabolite 4′-hydroxyphenyl carvedilol in human plasma using their deuterated internal standards (IS). Samples were prepared by solid-phase extraction using 100 μL human plasma. Chromatographic separation of analytes was achieved on UPLC C18 (50×2.1mm, 1.7μm) column using acetonitrile-4.0mm ammonium formate, pH3.0 adjusted with 0.1% formic acid (78:22, v/v) as the mobile phase. The multiple reaction monitoring transitions for both the analytes and IS were monitored in the positive electrospray ionization mode. The method was validated over a concentration range of 0.05-50ng/mL for carvedilol and 0.01-10ng/mL for 4′-hydroxyphenyl carvedilol. Intra- and inter-batch precision (% CV) and accuracy for the analytes varied from 0.74 to 3.88 and 96.4 to 103.3% respectively. Matrix effect was assessed by post-column analyte infusion and by calculation of precision values (coefficient of variation) in the measurement of the slope of calibration curves from eight plasma batches. The assay recovery was within 94-99% for both the analytes and IS. The method was successfully applied to support a bioequivalence study of 12.5mg carvedilol tablets in 34 healthy subjects. © 2013 John Wiley & Sons, Ltd.

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