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

Matthew D HillMaria-Jesus BlancoFrancesco G SalituroZhu BaiJacob T BeckleyMichael A AckleyJing DaiJames J DohertyBoyd L HarrisonEthan C HoffmannTatiana M KazdobaDavid LanzettaMichael LewisMichael C QuirkAlbert J Robichaud
Published in: Journal of medicinal chemistry (2022)
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.
Keyphrases
  • small molecule
  • cognitive impairment
  • clinical trial
  • pulmonary artery
  • high throughput
  • randomized controlled trial
  • phase ii
  • open label
  • blood brain barrier
  • systematic review
  • coronary artery
  • aortic dissection