神经活性类固醇
化学
γ-氨基丁酸受体
药理学
变构调节
受体
变构调节剂
别孕甾酮
神经科学
内科学
生物化学
心理学
医学
作者
Gabriel Martinez Botella,Francesco G. Salituro,Boyd L. Harrison,Richard T. Beresis,Zhu Bai,Marı́a-Jesús Blanco,Gabriel M. Belfort,Jing Dai,Carlos M. Loya,Michael A. Ackley,Alison L. Althaus,Scott J. Grossman,Ethan Hoffmann,James Doherty,Albert J. Robichaud
标识
DOI:10.1021/acs.jmedchem.7b00846
摘要
Certain classes of neuroactive steroids (NASs) are positive allosteric modulators (PAM) of synaptic and extrasynaptic GABAA receptors. Herein, we report new SAR insights in a series of 5β-nor-19-pregnan-20-one analogues bearing substituted pyrazoles and triazoles at C-21, culminating in the discovery of 3α-hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1′-yl)-19-nor-5β-pregnan-20-one (SAGE-217, 3), a potent GABAA receptor modulator at both synaptic and extrasynaptic receptor subtypes, with excellent oral DMPK properties. Compound 3 has completed a phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) clinical trial and is currently being studied in parallel phase 2 clinical trials for the treatment of postpartum depression (PPD), major depressive disorder (MDD), and essential tremor (ET).
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