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
  • 1. Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States. Electronic address: [email protected].
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).