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Your search keyword '"Hnin Hnin Khine"' showing total 6 results
Start Over Author "Hnin Hnin Khine" Topic chemistry, pharmaceutical
6 results on '"Hnin Hnin Khine"'

1. Discovery, SAR and X-ray structure of 1H-benzimidazole-5-carboxylic acid cyclohexyl-methyl-amides as inhibitors of inducible T-cell kinase (Itk)

Author

Michael P. Winters, Renee L. DesJarlais, Mark Bobko, John P. Wolak, Ho Yin Lo, Steven S. Pullen, Deborah D. Jeanfavre, Hnin Hnin Khine, Rosemarie H. Sallati, Ernest L. Raymond, Mohammed A. Kashem, Lei Qiao, Gregory P. Roth, Declan Ryan, Joseph R. Woska, Kevin J. Moriarty, Darius Robinson, Hidenori Takahashi, B. Tomczuk, Wilson Matthew Allan, Ronald L. Magolda, Peter Allen Nemoto, Andre White, and Brian Nicholas Cook

Subjects
Benzimidazole, Molecular model, medicine.drug_class, Stereochemistry, Chemistry, Pharmaceutical, Carboxylic acid, Clinical Biochemistry, Carboxylic Acids, Molecular Conformation, Pharmaceutical Science, Carboxamide, Crystallography, X-Ray, Biochemistry, Chemical synthesis, Inhibitory Concentration 50, Mice, Structure-Activity Relationship, chemistry.chemical_compound, Drug Discovery, medicine, Animals, Enzyme Inhibitors, skin and connective tissue diseases, Molecular Biology, chemistry.chemical_classification, biology, Bicyclic molecule, Kinase, fungi, Organic Chemistry, Protein-Tyrosine Kinases, Amides, body regions, Models, Chemical, chemistry, Enzyme inhibitor, Drug Design, Microsomes, Liver, biology.protein, Molecular Medicine, Benzimidazoles
Abstract

A series of novel potent benzimidazole based inhibitors of interleukin-2 T-cell kinase (Itk) were prepared. In this report, we discuss the structure-activity relationship (SAR), selectivity, and cell-based activity for the series. We also discuss the SAR associated with an X-ray structure of one of the small-molecule inhibitors bound to ITK.

Published
2008
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2. 5-Aminomethylbenzimidazoles as potent ITK antagonists

Author

Stanley Kugler, Mohammed A. Kashem, Ernest L. Raymond, Hidenori Takahashi, Steven S. Pullen, Leslie Martin, Gabriel Labissiere, Jennifer Ahlberg, Jennifer A. Kowalski, Hnin Hnin Khine, Joseph R. Woska, Stéphane De Lombaert, Donna Skow, David S. Thomson, Kathy O’Shea, Brian Nicholas Cook, Renee Zindell, Deborah D. Jeanfavre, Doris Riether, Jörg Bentzien, Kerry L. M. Ralph, and Rosemarie Sellati

Subjects
CD3 Complex, Stereochemistry, Chemistry, Pharmaceutical, Clinical Biochemistry, Pharmaceutical Science, Biochemistry, Rats, Sprague-Dawley, chemistry.chemical_compound, Inhibitory Concentration 50, Mice, Structure-Activity Relationship, Benzylamine, Amide, Drug Discovery, Potency, Structure–activity relationship, Moiety, Animals, Humans, Enzyme Inhibitors, Benzamide, Molecular Biology, chemistry.chemical_classification, Mice, Inbred BALB C, Organic Chemistry, Aromatic amine, Protein-Tyrosine Kinases, Rats, chemistry, Drug Design, Hepatocytes, Molecular Medicine, Benzimidazoles, Female, Linker
Abstract

Benzamide 1 demonstrated good potency as a selective ITK inhibitor, however the amide moiety was found to be hydrolytically labile in vivo, resulting in low oral exposure and the generation of mutagenic aromatic amine metabolites. Replacing the benzamide with a benzylamine linker not only addressed the toxicity issue, but also improved the cellular and functional potency as well as the drug-like properties. SAR studies around the benzylamines and the identification of 10n and 10o as excellent tools for proof-of-concept studies are described.

Published
2009

3. Discovery of potent inhibitors of interleukin-2 inducible T-cell kinase (ITK) through structure-based drug design

Author

John P. Wolak, Ji Wang, Hnin Hnin Khine, Peter Allen Nemoto, Chuk Chui Man, Stéphane De Lombaert, Steven S. Pullen, Hidenori Takahashi, Brian Nicholas Cook, Mohammed A. Kashem, Jörg Bentzien, Andre White, Gregory P. Roth, Fariba Soleymanzadeh, and Stanley Kugler

Subjects
Drug, Molecular model, Pyridines, media_common.quotation_subject, Chemistry, Pharmaceutical, Clinical Biochemistry, Amino Acid Motifs, Anti-Inflammatory Agents, Molecular Conformation, Pharmaceutical Science, Crystallography, X-Ray, Biochemistry, Inhibitory Concentration 50, Structure-Activity Relationship, Interleukin-2-Inducible T-Cell Kinase, Drug Discovery, Humans, Enzyme Inhibitors, Molecular Biology, media_common, chemistry.chemical_classification, Kinase, Chemistry, Organic Chemistry, Protein-Tyrosine Kinases, In vitro, Cell biology, Enzyme, Tec kinase, Models, Chemical, Drug Design, Molecular Medicine, Structure based, Benzimidazoles
Abstract

Interleukin-2 inducible T-cell kinase (ITK) is a member of the Tec kinase family and is involved with T-cell activation and proliferation. Due to its critical role in acting as a modulator of T-cells, ITK inhibitors could provide a novel route to anti-inflammatory therapy. This work describes the discovery of ITK inhibitors through structure-based design where high-resolution crystal structural information was used to optimize interactions within the kinase specificity pocket of the enzyme to improve both potency and selectivity.

Published
2008

4. Itk kinase inhibitors: initial efforts to improve the metabolical stability and the cell activity of the benzimidazole lead

Author

Gregory P. Roth, Hidenori Takahashi, Hnin Hnin Khine, Steven S. Pullen, Darius Robinson, Declan Ryan, Michael P. Winters, Lei Qiao, Lisa H. Liu, Ronald L. Magolda, Renee DesJarlis, Thomas M. Farrell, Paul Kaplita, Brian Nicholas Cook, Kevin J. Moriarty, Josephine King, and Mohammed A. Kashem

Subjects
Benzimidazole, Molecular model, CD3 Complex, medicine.drug_class, Chemistry, Pharmaceutical, T-Lymphocytes, Clinical Biochemistry, Pharmaceutical Science, Administration, Oral, Carboxamide, Crystallography, X-Ray, Biochemistry, chemistry.chemical_compound, Inhibitory Concentration 50, Structure-Activity Relationship, Adenosine Triphosphate, Drug Discovery, medicine, Potency, Humans, Enzyme Inhibitors, Molecular Biology, chemistry.chemical_classification, Binding Sites, biology, Organic Chemistry, Protein-Tyrosine Kinases, Enzyme, chemistry, Enzyme inhibitor, Drug Design, biology.protein, Microsome, Microsomes, Liver, Molecular Medicine, Benzimidazoles, Selectivity
Abstract

Previously, we reported a series of novel benzimidazole based Itk inhibitors that exhibited excellent enzymatic potency and selectivity but low microsomal stability. Employing a structure based approach a new series of inhibitors with comparable potency and selectivity to the original series and with a potential for improved microsome stability was identified.

Published
2008

5. 5-Aminomethyl-1H-benzimidazoles as orally active inhibitors of inducible T-cell kinase (Itk)

Author

Michael P. Winters, Renee L. DesJarlais, Paul Kaplita, Hnin Hnin Khine, Kevin J. Moriarty, Steven S. Pullen, Ernest L. Raymond, Roger J. Snow, Rosemarie Sellati, Gregory P. Roth, Charles L. Cywin, Thomas M. Farrell, Lisa H. Liu, Mohammed A. Kashem, Hidenori Takahashi, Darius Robinson, Joseph R. Woska, Josephine King, and John P. Wolak

Subjects
Benzimidazole, Tertiary amine, CD3 Complex, medicine.medical_treatment, Chemistry, Pharmaceutical, T-Lymphocytes, Clinical Biochemistry, Pharmaceutical Science, Administration, Oral, Lymphocyte Activation, Biochemistry, chemistry.chemical_compound, Inhibitory Concentration 50, Mice, Structure-Activity Relationship, In vivo, Drug Discovery, medicine, Animals, Humans, Molecular Biology, chemistry.chemical_classification, Mice, Inbred BALB C, biology, Organic Chemistry, Protein-Tyrosine Kinases, In vitro, Enzyme, Cytokine, chemistry, Models, Chemical, Enzyme inhibitor, Drug Design, biology.protein, Molecular Medicine, Benzimidazoles, Signal transduction
Abstract

A series of novel 5-aminomethyl-1H-benzimidazole based inhibitors of Itk were prepared. Structure–activity relationships, selectivity and cell activity are reported for this series. Compound 2, a potent and selective antagonist of Itk, inhibited anti-CD3 antibody induced IL-2 production in vivo in mice.

Published
2008

6. Hit-to-lead studies on benzimidazole inhibitors of ITK: discovery of a novel class of kinase inhibitors

Author

Hnin Hnin Khine, Christopher Ronald Sarko, Mohammed A. Kashem, Noel S. Wilson, John P. Wolak, Josephine King, Teresa Roma, Charles L. Cywin, Jennifer A. Kowalski, Scot Campbell, John Lord, Steven S. Pullen, Michael P. Winters, Gregory P. Roth, Asitha Abeywardane, and Roger J. Snow

Subjects
Benzimidazole, Stereochemistry, High-throughput screening, Chemistry, Pharmaceutical, Clinical Biochemistry, Drug Evaluation, Preclinical, Pharmaceutical Science, Plasma protein binding, Biochemistry, chemistry.chemical_compound, Inhibitory Concentration 50, Structure-Activity Relationship, Adenosine Triphosphate, Drug Discovery, Structure–activity relationship, Humans, Binding site, Enzyme Inhibitors, Molecular Biology, Protein Kinase Inhibitors, chemistry.chemical_classification, Binding Sites, biology, Organic Chemistry, Hydrogen Bonding, Hit to lead, Protein-Tyrosine Kinases, Enzyme, chemistry, Models, Chemical, Enzyme inhibitor, biology.protein, Molecular Medicine, Benzimidazoles, Protein Binding
Abstract

Benzimidazole 1 was identified as a selective inhibitor of ITK by high throughput screening. Hit-to-lead studies defined the SAR at all three substituents. Reversing the amide linkage at C6 led to 16, with a fivefold improvement of potency. This enhancement is rationalized by the conformational preference of the substituent. A model for the binding of the benzimidazoles to the ATP-binding site of ITK is proposed.

Published
2007

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