2-(Pyridin-3-yl)quinazoline compounds as glucocerebrosidase modulators

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PROPOSED TITLE: 2-(Pyridin-3-yl) quinazoline Compounds as Glucocerebrosidase Modulators

NU 2015-064

INVENTORS

  • Richard Silverman*
  • Dimitri Krainc
  • Jianbin Zheng

SHORT DESCRIPTION

Novel substituted quinazoline compounds that modulate glucocerebrosidase activity, offering a promising therapeutic approach for neurodegenerative disorders such as Gaucher’s disease and Parkinson’s disease.

BACKGROUND

The invention relates to new small molecules featuring a substituted quinazoline core designed to modulate glucocerebrosidase (GCase) activity. Deficiencies or aberrations in GCase—stemming from mutations in the GBA1 gene—are implicated in diseases like Gaucher’s and Parkinson’s, where current therapies (e.g., enzyme replacement) have limitations. These modulators address unmet clinical needs by offering improved chemical properties and the potential to function as pharmacological chaperones, as well as diagnostic fluorescent probes in high throughput screening assays.

ABSTRACT

Disclosed are novel 2-(pyridin-3-yl)quinazoline compounds that modulate glucocerebrosidase activity through binding interactions that can either inhibit or activate the enzyme. The compounds exhibit enhanced solubility, optimal polar surface area, and increased binding affinity compared to previous active-site inhibitors. They may be formulated in pharmaceutical compositions for the treatment or prevention of neurodegenerative diseases associated with aberrant GCase activity, and can be conjugated with fluorophores for use as diagnostic probes in high throughput screening.

APPLICATIONS

  • Treatment of Gaucher’s disease and other lysosomal storage disorders.
  • Treatment of Parkinson’s disease and related neurodegenerative disorders.
  • High throughput screening for novel GCase modulators using fluorescent probe applications.

ADVANTAGES

  • Novel quinazoline scaffold with improved physicochemical properties.
  • Dual modulatory capability allowing both GCase activation and inhibition.
  • Enhanced solubility, polar surface area, and binding affinity compared to active-site targeted compounds.
  • Versatile design enables both therapeutic and diagnostic applications.

PUBLICATIONS

Richard Silverman et al., Design and Synthesis of Potent Quinazolines as Selective β-Glucocerebrosidase Modulators, Journal of Medicinal Chemistry, May 2016

IP STATUS

Issued US Patent US10167270B2

Patent Information: