2. Academic Validation
  3. SAGE-718: A First-in-Class N-Methyl-d-Aspartate Receptor Positive Allosteric Modulator for the Potential Treatment of Cognitive Impairment

SAGE-718: A First-in-Class N-Methyl-d-Aspartate Receptor Positive Allosteric Modulator for the Potential Treatment of Cognitive Impairment

  • J Med Chem. 2022 Jul 14;65(13):9063-9075. doi: 10.1021/acs.jmedchem.2c00313.
Matthew D Hill 1,  Maria-Jesus Blanco 1,  Francesco G Salituro 1,  Zhu Bai 1,  Jacob T Beckley 1,  Michael A Ackley 1,  Jing Dai 1,  James J Doherty 1,  Boyd L Harrison 1,  Ethan C Hoffmann 1,  Tatiana M Kazdoba 1,  David Lanzetta 1,  Michael Lewis 1,  Michael C Quirk 1,  Albert J Robichaud 1
Affiliations

Affiliation

  • 1 Sage Therapeutics, Inc., 215 First Street, Cambridge, Massachusetts 02142, United States.
PMID: 35785990 DOI: 10.1021/acs.jmedchem.2c00313
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.

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