2. Academic Validation
  3. Discovery and Optimization of Selective Brain-Penetrant EBP Inhibitors that Enhance Oligodendrocyte Formation

Discovery and Optimization of Selective Brain-Penetrant EBP Inhibitors that Enhance Oligodendrocyte Formation

  • J Med Chem. 2024 Mar 12. doi: 10.1021/acs.jmedchem.3c02396.
Ruth Dorel 1,  Dawei Sun 1,  Nicholas Carruthers 2,  Georgette M Castanedo 1,  Peter M-U Ung 1,  Daniel C Factor 2,  Tianbo Li 1,  Hannah Baumann 2,  Danielle Janota 2,  Jodie Pang 1,  Laurent Salphati 1,  Robert Meklemburg 2,  Allison J Korman 2,  Halie E Harper 2,  Samantha Stubblefield 2,  Jian Payandeh 1,  Daniel McHugh 2,  Bradley T Lang 2,  Paul J Tesar 2,  Edward Dere 1,  Matthieu Masureel 1,  Drew J Adams 2,  Matthew Volgraf 1,  Marie-Gabrielle Braun 1
Affiliations

Affiliations

  • 1 Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 2 Convelo Therapeutics, 11000 Cedar Avenue, Cleveland, Ohio 44106, United States.
PMID: 38470227 DOI: 10.1021/acs.jmedchem.3c02396
Abstract

The inhibition of emopamil binding protein (EBP), a sterol isomerase within the Cholesterol biosynthesis pathway, promotes oligodendrocyte formation, which has been proposed as a potential therapeutic approach for treating multiple sclerosis. Herein, we describe the discovery and optimization of brain-penetrant, orally bioavailable inhibitors of EBP. A structure-based drug design approach from literature compound 1 led to the discovery of a hydantoin-based scaffold, which provided balanced physicochemical properties and potency and an improved in vitro safety profile. The long half-lives of early hydantoin-based EBP inhibitors in rodents prompted an unconventional optimization strategy, focused on increasing metabolic turnover while maintaining potency and a brain-penetrant profile. The resulting EBP inhibitor 11 demonstrated strong in vivo target engagement in the brain, as illustrated by the accumulation of EBP substrate zymostenol after repeated dosing. Furthermore, compound 11 enhanced the formation of oligodendrocytes in human cortical organoids, providing additional support for our therapeutic hypothesis.

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