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Hwaseong, South Korea

Jin H.-E.,Seoul National University | Kim Y.C.,CandC Research Laboratories | Maeng H.-J.,Inje University
Journal of Pharmaceutical Investigation | Year: 2014

A simple and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the positive electrospray ionization mode was developed and validated in order to analyze cefaclor, a second generation cephalosporin antibiotic, in rat plasma. The plasma was pre-treated by a single step of protein precipitation with methanol, and then injected directly into the LC/MS/MS system for quantification. Drugs were separated on a Synergi 4μ Polar-RP 80 A column (150 × 2.0 mm) with a mixture of 0.1 % formic acid and methanol (65: 35, v/v) as the mobile phase at 0.2 mL/min. Detection was performed with multiple reaction-monitoring modes at m/z 368.1 → 174.2 (for cefaclor) and m/z 396.0 → 227.1 (for cefdinir, the internal standard). The limit of quantification (LOQ) was determined to be 10 ng/mL with acceptable linearity ranging from 10 to 10,000 ng/mL. Validation parameters for cefaclor, including accuracy, precision, absolute matrix effect, and stability in rat plasma, were acceptable according to the assay validation guidelines of the FDA (U.S. Department of Health & Human Services, Food and Drug Administration, Guidance for Industry, Bioanalytical Method Validation, 2001). The developed analytical method was successfully applied to the pharmacokinetic studies of cefaclor in rats. These observations suggest, therefore, that the validated assay can be used in routine pharmacokinetic studies of cefaclor in rats. © 2013 The Korean Society of Pharmaceutical Sciences and Technology. Source

Kinoshita K.,Chugai Pharmaceutical Co. | Kobayashi T.,Chugai Pharmaceutical Co. | Asoh K.,Chugai Pharmaceutical Co. | Furuichi N.,Chugai Pharmaceutical Co. | And 13 more authors.
Journal of Medicinal Chemistry | Year: 2011

9-Substituted 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles were discovered as highly selective and potent anaplastic lymphoma kinase (ALK) inhibitors by structure-based drug design. The high target selectivity was achieved by introducing a substituent close to the E0 region of the ATP binding site, which has a unique amino acid sequence. Among the identified inhibitors, compound 13d showed highly selective and potent inhibitory activity against ALK with an IC50 value of 2.9 nM and strong antiproliferative activity against KARPAS-299 with an IC50 value of 12.8 nM. The compound also displayed significant antitumor efficacy in an established ALK fusion gene-positive anaplastic large-cell lymphoma (ALCL) xenograft model in mice without body weight loss. © 2011 American Chemical Society. Source

Miura T.,Chugai Pharmaceutical Co. | Fukami T.A.,Chugai Pharmaceutical Co. | Hasegawa K.,Chugai Pharmaceutical Co. | Ono N.,Chugai Pharmaceutical Co. | And 9 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2011

Heat shock protein 90 (Hsp90) is a molecular chaperone which regulates maturation and stabilization of its substrate proteins, known as client proteins. Many client proteins of Hsp90 are involved in tumor progression and survival and therefore Hsp90 can be a good target for developing anticancer drugs. With the aim of efficiently identifying a new class of orally available inhibitors of the ATP binding site of this protein, we conducted fragment screening and virtual screening in parallel against Hsp90. This approach quickly identified 2-aminotriazine and 2-aminopyrimidine derivatives as specific ligands to Hsp90 with high ligand efficiency. In silico evaluation of the 3D X-ray Hsp90 complex structures of the identified hits allowed us to promptly design CH5015765, which showed high affinity for Hsp90 and antitumor activity in human cancer xenograft mouse models. © 2011 Elsevier Ltd. All rights reserved. Source

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