2. Academic Validation
  3. Discovery of the Oxadiazine FRM-024: A Potent CNS-Penetrant Gamma Secretase Modulator

Discovery of the Oxadiazine FRM-024: A Potent CNS-Penetrant Gamma Secretase Modulator

  • J Med Chem. 2021 Oct 14;64(19):14426-14447. doi: 10.1021/acs.jmedchem.1c00904.
Matthew G Bursavich 1,  Bryce A Harrison 1,  Raksha Acharya 1,  Donald E Costa 1,  Emily A Freeman 1,  Lori A Hrdlicka 1,  Hong Jin 1,  Sudarshan Kapadnis 1,  Jeffrey S Moffit 1,  Deirdre Murphy 1,  Scott J Nolan 1,  Holger Patzke 1,  Cuyue Tang 1,  Hilliary E Van Voorhies 1,  Melody Wen 1,  Gerhard Koenig 1,  Jean-François Blain 1,  Duane A Burnett 1
Affiliations

Affiliation

  • 1 FORUM Pharmaceuticals, 225 Second Avenue, Waltham, Massachusetts 02451, United States.
PMID: 34550687 DOI: 10.1021/acs.jmedchem.1c00904
Abstract

The recent approval of aducanumab for Alzheimer's disease has heightened the interest in therapies targeting the amyloid hypothesis. Our research has focused on identification of novel compounds to improve amyloid processing by modulating gamma secretase activity, thereby addressing a significant biological deficit known to plague the familial form of the disease. Herein, we describe the design, synthesis, and optimization of new gamma secretase modulators (GSMs) based on previously reported oxadiazine 1. Potency improvements with a focus on predicted and measured properties afforded high-quality compounds further differentiated via robust Aβ42 reductions in both rodents and nonhuman primates. Extensive preclinical profiling, efficacy studies, and safety studies resulted in the nomination of FRM-024, (+)-cis-5-(4-chlorophenyl)-6-cyclopropyl-3-(6-methoxy-5-(4-methyl-1H-imidazole-1-yl)pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine, as a GSM preclinical candidate for familial Alzheimer's disease.

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