Bioorganic and Medicinal Chemistry Letters p. 6447 - 6454 (2013)
Update date:2022-07-29
Topics:
Chen, Jian Jeffrey
Qian, Wenyuan
Biswas, Kaustav
Yuan, Chester
Amegadzie, Albert
Liu, Qingyian
Nixey, Thomas
Zhu, Joe
Ncube, Mqhele
Rzasa, Robert M.
Chavez, Frank
Chen, Ning
Demorin, Frenel
Rumfelt, Shannon
Tegley, Christopher M.
Allen, Jennifer R.
Hitchcock, Stephen
Hungate, Randy
Bartberger, Michael D.
Zalameda, Leeanne
Liu, Yichin
McCarter, John D.
Zhang, Jianhua
Zhu, Li
Babu-Khan, Safura
Luo, Yi
Bradley, Jodi
Wen, Paul H.
Reid, Darren L.
Koegler, Frank
Dean Jr., Charles
Hickman, Dean
Correll, Tiffany L.
Williamson, Toni
Wood, Stephen
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.
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