SAGE-718: A First-in-Class<i>N</i>-Methyl-<scp>d</scp>-Aspartate Receptor Positive Allosteric Modulator for the Potential Treatment of Cognitive Impairment
Matthew D. Hill, María‐Jesús Blanco, Francesco G. Salituro, Zhu Bai, Jacob T. Beckley, Michael A. Ackley, Jing Dai, James Doherty, Boyd L. Harrison, Ethan Hoffmann, Tatiana M. Kazdoba, David Lanzetta, Michael Lewis, Michael C. Quirk, Albert J. Robichaud
Abstract
N-Methyl-d-aspartate receptor (NMDAR) positive allosteric modulators (PAMs) have received increased interest as a powerful mechanism of action to provide relief as therapies for CNS disorders. Sage Therapeutics has previously published the discovery of endogenous neuroactive steroid 24(S)-hydroxycholesterol as an NMDAR PAM. In this article, we detail the discovery of development candidate SAGE-718 (5), a potent and high intrinsic activity NMDAR PAM with an optimized pharmacokinetic profile for oral dosing. Compound 5 has completed phase 1 single ascending dose and multiple ascending dose clinical trials and is currently undergoing phase 2 clinical trials for treatment of cognitive impairment in Huntington’s disease.