Discovery of 2-methylpyridine-based biaryl amides as γ-secretase modulators for the treatment of Alzheimer’s disease
| Autor: | Qingyian Liu, Kaustav Biswas, Frank Koegler, Tiffany L. Correll, Toni Williamson, Jodi Bradley, Jennifer R. Allen, Leeanne Zalameda, Darren L. Reid, Michael D. Bartberger, Joe Zhu, Stephen J. Wood, Randy Hungate, Yichin Liu, Frank Chavez, Robert M. Rzasa, Jianhua Zhang, John D. McCarter, Thomas Nixey, Paul H. Wen, Li Zhu, Shannon Rumfelt, Yi Luo, Safura Babu-Khan, Stephen Hitchcock, Ning Chen, Mqhele Ncube, Wenyuan Qian, Frenel Fils Demorin, Dean Hickman, Christopher M. Tegley, Jian J. Chen, Albert Amegadzie, Charles W. Dean, Chester Chenguang Yuan |
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| Rok vydání: | 2013 |
| Předmět: |
Enzyme complex
Clinical Biochemistry Cell Pharmaceutical Science Pharmacology Cleavage (embryo) Biochemistry Rats Sprague-Dawley Cerebrospinal fluid Alzheimer Disease Oral administration Drug Discovery medicine Animals Humans Potency Molecular Biology Cell potency chemistry.chemical_classification Organic Chemistry Amides Rats HEK293 Cells Enzyme medicine.anatomical_structure chemistry Picolines Molecular Medicine Amyloid Precursor Protein Secretases |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 23:6447-6454 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2013.09.041 |
| Popis: | γ-Secretase modulators (GSMs) are potentially disease-modifying treatments for Alzheimer's disease. They selectively lower pathogenic Aβ42 levels by shifting the enzyme cleavage sites without inhibiting γ-secretase activity, possibly avoiding known adverse effects observed with complete inhibition of the enzyme complex. A cell-based HTS effort identified the sulfonamide 1 as a GSM lead. Lead optimization studies identified compound 25 with improved cell potency, PKDM properties, and it lowered Aβ42 levels in the cerebrospinal fluid (CSF) of Sprague-Dawley rats following oral administration. Further optimization of 25 to improve cellular potency is described. |
| Databáze: | OpenAIRE |
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