2. Academic Validation
  3. Design and synthesis of novel methoxypyridine-derived gamma-secretase modulators

Design and synthesis of novel methoxypyridine-derived gamma-secretase modulators

  • Bioorg Med Chem. 2020 Nov 15;28(22):115734. doi: 10.1016/j.bmc.2020.115734.
Kevin D Rynearson 1,  Ronald N Buckle 2,  R Jason Herr 2,  Nicholas J Mayhew 2,  Xinchao Chen 2,  William D Paquette 2,  Samuel A Sakwa 2,  Jinhai Yang 2,  Keith D Barnes 2,  Phuong Nguyen 3,  William C Mobley 3,  Graham Johnson 4,  Juinn H Lin 5,  Rudolph E Tanzi 6,  Steven L Wagner 7
Affiliations

Affiliations

  • 1 Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093-0624, United States. Electronic address: krynearson@ucsd.edu.
  • 2 Department of Medicinal Chemistry, AMRI, East Campus, 3 University Place, Rensselaer, NY 12144, United States.
  • 3 Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093-0624, United States.
  • 4 NuPharmAdvise, 3 Lakeside Drive, Sanbornton, NH 03269, United States.
  • 5 Biopharm Consulting Partners, 2 Willet Drive, Ambler, PA 19002, United States.
  • 6 Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, United States.
  • 7 Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093-0624, United States; Veterans Administrative San Diego Healthcare System, La Jolla, CA 92161, United States. Electronic address: slwagner@health.ucsd.edu.
PMID: 33007551 DOI: 10.1016/j.bmc.2020.115734
Abstract

The evolution of gamma-secretase modulators (GSMs) through the introduction of novel heterocycles with the goal of aligning activity for reducing the levels of Aβ42 and properties consistent with a drug-like molecule are described. The insertion of a methoxypyridine motif within the tetracyclic scaffold provided compounds with improved activity for arresting Aβ42 production as well as improved properties, including solubility. In vivo pharmacokinetic analysis demonstrated that several compounds within the novel series were capable of crossing the BBB and accessing the therapeutic target. Treatment with methoxypyridine-derived compound 64 reduced Aβ42 levels in the plasma of J20 mice, in addition to reducing Aβ42 levels in the plasma and brain of Tg2576 mice.

Keywords

Alzheimer’s disease; Amyloid beta; Aβ42 reduction; Gamma secretase modulator; Methoxypyridines; Structure activity relationship.

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