Bioorganic & medicinal chemistry, 2008-04, Vol.16 (8), p.4699-4714
2008
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Details
- Autor(en) / Beteiligte
- Titel
- Discovery, synthesis and biological evaluation of isoquinolones as novel and highly selective JNK inhibitors ( 2)
- Ist Teil von
- Bioorganic & medicinal chemistry, 2008-04, Vol.16 (8), p.4699-4714
- Ort / Verlag
- Oxford: Elsevier Ltd
- Erscheinungsjahr
- 2008
- Quelle
- Access via ScienceDirect (Elsevier)
- Beschreibungen/Notizen
- 3-Metoxycarbonyl isoquinolone derivative 1 has been identified as a potent JNK inhibitor and significantly inhibited cardiac hypertrophy in a rat pressure-overload model. Herein, a series of isoquinolones with an imidazolylmethyl or a pyrazolylmethyl group at the 2-position were designed based on X-ray crystallographic analysis of the complex between the isoquinolone compound and JNK3, as wells as the relationship between compound lipophilicity (log D) and activity in a cell-based assay. The compounds prepared showed potent JNK1 inhibitory activities in a cell-based assay. Among them the isoquinolone derivative possessing 5-[(cyclopropylamino)carbonyl]-1-methyl-1 H-pyrazole ( 16e) exhibited significant anti-hypertrophic activity at doses of more than 1 mg/kg (po) in a pressure-overload model.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0968-0896eISSN: 1464-3391DOI: 10.1016/j.bmc.2008.02.028Titel-ID: cdi_proquest_miscellaneous_69127839
- Format
- –
- Schlagworte
- Alcohols - chemistry, Aldehydes - chemistry, Animals, Biological and medical sciences, Cardiovascular system, Cell Line, Crystallography, X-Ray, Enzyme Inhibitors - chemical synthesis, Enzyme Inhibitors - chemistry, Enzyme Inhibitors - pharmacology, H9c2 cell, In vivo efficacy, Isoquinolines - chemical synthesis, Isoquinolines - chemistry, Isoquinolines - pharmacology, Isoquinolone derivatives, JNK, JNK inhibitor, JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors, JNK Mitogen-Activated Protein Kinases - chemistry, JNK Mitogen-Activated Protein Kinases - metabolism, log D value, Male, Medical sciences, Miscellaneous, Models, Molecular, Molecular Structure, Pharmacology. Drug treatments, Rats, Rats, Wistar, SAR, Structure-Activity Relationship, X-ray crystallography