2. Academic Validation
  3. Discovery of brain permeable 2-Azabicyclo[2.2.2]octane sulfonamides as a novel class of presenilin-1 selective γ-secretase inhibitors

Discovery of brain permeable 2-Azabicyclo[2.2.2]octane sulfonamides as a novel class of presenilin-1 selective γ-secretase inhibitors

  • Eur J Med Chem. 2023 Nov 15;260:115725. doi: 10.1016/j.ejmech.2023.115725.
Rajeshwar Narlawar 1,  Lutgarde Serneels 2,  Celia Gaffric 3,  Harrie J M Gijsen 3,  Bart De Strooper 4,  François Bischoff 5
Affiliations

Affiliations

  • 1 Discovery Chemistry, Therapeutics Discovery, Janssen Research & Development, Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340, Beerse, Belgium; KU Leuven, Department of Neurosciences, Leuven Institute for Neuroscience and Disease, (LIND), Leuven, Belgium. Electronic address: [email protected].
  • 2 VIB Center for Brain and Disease Research, Leuven, Belgium.
  • 3 Discovery Chemistry, Therapeutics Discovery, Janssen Research & Development, Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340, Beerse, Belgium.
  • 4 KU Leuven, Department of Neurosciences, Leuven Institute for Neuroscience and Disease, (LIND), Leuven, Belgium; VIB Center for Brain and Disease Research, Leuven, Belgium; Dementia Research Institute, University College London, London, UK.
  • 5 Discovery Chemistry, Therapeutics Discovery, Janssen Research & Development, Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340, Beerse, Belgium. Electronic address: [email protected].
PMID: 37657269 DOI: 10.1016/j.ejmech.2023.115725
Abstract

This paper describes the rational design, synthesis, structure-activity relationship (SAR), and biological profile of presenilin-1 (PSEN-1) complex selective γ-secretase inhibitors, assessed for selectivity using a unique set of four γ-secretase subtype complexes. A set of known PSEN-1 selective γ-secretase inhibitors (GSIs) was analyzed to understand the pharmacophoric features required for selective inhibition. Conformational modeling suggests that a characteristic 'U' shape orientation between aromatic sulfone/sulfonamide and aryl ring is crucial for PSEN-1 selectivity and potency. Using these insights, a series of brain-penetrant 2-azabicyclo[2,2,2]octane sulfonamides was devised and synthesized as a new class of PSEN-1 selective inhibitors. Compounds 13c and 13k displayed high potency towards PSEN1-APH1B complex but moderate selectivity towards PSEN2 complexes. However, compound (+)-13b displayed low nanomolar potency towards the PSEN1-APH1B complex, little (∼4-fold) selectivity towards PSEN1-APH1A, and high selectivity (>350-fold) versus PSEN2 complexes. Excellent brain penetration, no significant CYP inhibition, or cardiotoxicity, good solubility, and permeability make (+)-13b an excellent candidate for further lead optimization.

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