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3-Amino-pyrazolo[3,4-d]pyrimidines as p38α kinase inhibitors: design and development to a highly selective lead. 2011

Michael Soth, and Sarah Abbot, and Allassan Abubakari, and Nidhi Arora, and Humberto Arzeno, and Roland Billedeau, and Nolan Dewdney, and Kieran Durkin, and Sandra Frauchiger, and Manjiri Ghate, and David M Goldstein, and Ronald J Hill, and Andreas Kuglstatter, and Fujun Li, and Brad Loe, and Kristen McCaleb, and Joel McIntosh, and Eva Papp, and Jaehyeon Park, and Martin Stahl, and Man-Ling Sung, and Rebecca Suttman, and David C Swinney, and Paul Weller, and Brian Wong, and Hasim Zecic, and Tobias Gabriel
Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94304, USA. michael.soth@roche.com

Learnings from previous Roche p38-selective inhibitors were applied to a new fragment hit, which was optimized to a potent, exquisitely selective preclinical lead with a good pharmacokinetic profile.

UI MeSH Term Description Entries
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D011720 Pyrazoles Azoles of two nitrogens at the 1,2 positions, next to each other, in contrast with IMIDAZOLES in which they are at the 1,3 positions.
D011743 Pyrimidines A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (CYTOSINE; THYMINE; and URACIL) and form the basic structure of the barbiturates.
D004789 Enzyme Activation Conversion of an inactive form of an enzyme to one possessing metabolic activity. It includes 1, activation by ions (activators); 2, activation by cofactors (coenzymes); and 3, conversion of an enzyme precursor (proenzyme or zymogen) to an active enzyme. Activation, Enzyme,Activations, Enzyme,Enzyme Activations
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D015195 Drug Design The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis. Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs
D015394 Molecular Structure The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. Structure, Molecular,Molecular Structures,Structures, Molecular
D048308 Mitogen-Activated Protein Kinase 14 A 38-kDa mitogen-activated protein kinase that is abundantly expressed in a broad variety of cell types. It is involved in the regulation of cellular stress responses as well as the control of proliferation and survival of many cell types. The kinase activity of the enzyme is inhibited by the pyridinyl-imidazole compound SB 203580. CSAID-Binding Protein,Cytokine Suppressive Anti-inflammatory Drug Binding Protein,Kinase CSBP,MAPK14,MAPK14 Mitogen-Activated Protein Kinase,MAX-Interacting Protein 2,Mxi2 Protein,SAPK2a,Stress-activated protein kinase 2a,p38alpha MAP Kinase,p38alpha Mitogen-Activated Protein Kinase,p38alphaMAPK,CSAID Binding Protein,CSBP, Kinase,Cytokine Suppressive Anti inflammatory Drug Binding Protein,MAP Kinase, p38alpha,MAPK14 Mitogen Activated Protein Kinase,MAX Interacting Protein 2,Mitogen Activated Protein Kinase 14,Stress activated protein kinase 2a,p38alpha Mitogen Activated Protein Kinase
D051381 Rats The common name for the genus Rattus. Rattus,Rats, Laboratory,Rats, Norway,Rattus norvegicus,Laboratory Rat,Laboratory Rats,Norway Rat,Norway Rats,Rat,Rat, Laboratory,Rat, Norway,norvegicus, Rattus

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