变构调节
NMDA受体
神经活性类固醇
变构调节剂
药理学
化学
药代动力学
加药
受体
神经科学
作用机理
心理学
体外
生物化学
医学
γ-氨基丁酸受体
作者
Matthew D Hill,Marı́a-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
标识
DOI:10.1021/acs.jmedchem.2c00313
摘要
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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