Neuroactive Steroid N-Methyl-d-aspartate Receptor Positive Allosteric Modulators: Synthesis, SAR, and Pharmacological Activity

J Med Chem. 2019 Aug 22;62(16):7526-7542. doi: 10.1021/acs.jmedchem.9b00591.

Daniel S La ¹, Francesco G Salituro ¹, Gabriel Martinez Botella ¹, Andrew M Griffin ¹, Zhu Bai ², Michael A Ackley ¹, Jing Dai ¹, James J Doherty ¹, Boyd L Harrison ¹, Ethan C Hoffmann ¹, Tatiana M Kazdoba ¹, Michael C Lewis ¹, Michael C Quirk ¹, Albert J Robichaud ¹

Affiliations

1 SAGE Therapeutics , 215 First Street , Cambridge , Massachusetts 02142 , United States.
2 Wuxi AppTec , 288 Fute Zhong Road , Shanghai 200131 , China.

PMID: 31390523 DOI: 10.1021/acs.jmedchem.9b00591

Abstract

Neuroactive Steroids (NASs) play a pivotal role in maintaining homeostasis is the CNS. We have discovered that one NAS in particular, 24(S)-hydroxycholesterol (24(S)-HC), is a positive allosteric modulator (PAM) of NMDA receptors. Using 24(S)-HC as a chemical starting point, we have identified Other NASs that have good in vitro potency and efficacy. Herein, we describe the structure activity relationship and pharmacokinetic optimization of this series that ultimately led to SGE-301 (42). We demonstrate that SGE-301 enhances long-term potentiation (LTP) in rat hippocampal slices and, in a dose-dependent manner, improves cognition in a rat social recognition study.

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