Discovery of 2-methylpyridine-based biaryl amides as γ-secretase modulators for the treatment of Alzheimer's disease

Bioorg Med Chem Lett. 2013 Dec 1;23(23):6447-54. doi: 10.1016/j.bmcl.2013.09.041.

Jian Jeffrey Chen ¹, Wenyuan Qian, Kaustav Biswas, Chester Yuan, Albert Amegadzie, Qingyian Liu, Thomas Nixey, Joe Zhu, Mqhele Ncube, Robert M Rzasa, Frank Chavez Jr, Ning Chen, Frenel DeMorin, Shannon Rumfelt, Christopher M Tegley, Jennifer R Allen, Stephen Hitchcock, Randy Hungate, Michael D Bartberger, Leeanne Zalameda, Yichin Liu, John D McCarter, Jianhua Zhang, Li Zhu, Safura Babu-Khan, Yi Luo, Jodi Bradley, Paul H Wen, Darren L Reid, Frank Koegler, Charles Dean Jr, Dean Hickman, Tiffany L Correll, Toni Williamson, Stephen Wood

Affiliations

Affiliation

1 Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States. Electronic address: jianc@amgen.com.

PMID: 24139583 DOI: 10.1016/j.bmcl.2013.09.041

Abstract

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.

Keywords

Alzheimer’s disease (AD); Amide as sulfonamide replacement; Amyloid β-protein (Aβ); Methylpyridine; γ-Secretase inhibitor (GSI); γ-Secretase modulator (GSM).

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