Pyrazole-based arylalkyne cathepsin S inhibitors. Part II: optimization of cellular potency
| Autor: | Elizabeth Ann Gleason, Lars Karlsson, Hui Cai, Damara Gebauer, James P. Edwards, Yin Gu, Siquan Sun, Michael K. Ameriks, Jian Zhu, Robin L. Thurmond, Steven Nguyen |
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| Rok vydání: | 2009 |
| Předmět: |
Stereochemistry
Clinical Biochemistry Pharmaceutical Science Pyrazole Biochemistry Cell Line chemistry.chemical_compound Mice Structure-Activity Relationship Piperidines Morpholine Drug Discovery Potency Animals Humans Protease Inhibitors Molecular Biology IC50 Cathepsin S chemistry.chemical_classification Bicyclic molecule Organic Chemistry Cathepsins Enzyme chemistry Drug Design Molecular Medicine Pyrazoles Pharmacophore |
| Zdroj: | Bioorganicmedicinal chemistry letters. 19(21) |
| ISSN: | 1464-3405 |
| Popis: | Basic lipophilic substituents dramatically improved the cellular potency of a previously disclosed series of pyrazole-based arylalkyne cathepsin S inhibitors. The incorporation of substituted benzylamines in the para position of the arylalkyne maintained enzymatic activity (hCatS IC50=80-420 nM) and imparted cellular potency (IC50=0.8-4.0 microM). Further refinement of the morpholine portion of the pharmacophore enabled the identification of bicyclic piperidines with enhanced affinity for CatS (IC50=10-30 nM) and sub-micromolar cellular potency (JY Ii IC50=200-720 nM). |
| Databáze: | OpenAIRE |
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