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Neuroactive Steroids. 1. Positive Allosteric Modulators of the (γ-Aminobutyric Acid)A Receptor: Structure-Activity Relationships of Heterocyclic Substitution at C-21.
Martinez Botella, Gabriel; Salituro, Francesco G; Harrison, Boyd L; Beresis, Richard T; Bai, Zhu; Shen, Kaisheng; Belfort, Gabriel M; Loya, Carlos M; Ackley, Michael A; Grossman, Scott J; Hoffmann, Ethan; Jia, Shiling; Wang, Jiamiao; Doherty, James J; Robichaud, Albert J.
Affiliation
  • Martinez Botella G; †SAGE Therapeutics, 215 First Street, Cambridge, Massachusetts 02142, United States.
  • Salituro FG; †SAGE Therapeutics, 215 First Street, Cambridge, Massachusetts 02142, United States.
  • Harrison BL; †SAGE Therapeutics, 215 First Street, Cambridge, Massachusetts 02142, United States.
  • Beresis RT; ‡Shanghai Chempartner, 998 Halei Road, Shanghai, China 201203.
  • Bai Z; §WuXi AppTec, 288 Fute Zhong Road, Shanghai, China 200131.
  • Shen K; ‡Shanghai Chempartner, 998 Halei Road, Shanghai, China 201203.
  • Belfort GM; †SAGE Therapeutics, 215 First Street, Cambridge, Massachusetts 02142, United States.
  • Loya CM; †SAGE Therapeutics, 215 First Street, Cambridge, Massachusetts 02142, United States.
  • Ackley MA; †SAGE Therapeutics, 215 First Street, Cambridge, Massachusetts 02142, United States.
  • Grossman SJ; †SAGE Therapeutics, 215 First Street, Cambridge, Massachusetts 02142, United States.
  • Hoffmann E; †SAGE Therapeutics, 215 First Street, Cambridge, Massachusetts 02142, United States.
  • Jia S; ‡Shanghai Chempartner, 998 Halei Road, Shanghai, China 201203.
  • Wang J; ‡Shanghai Chempartner, 998 Halei Road, Shanghai, China 201203.
  • Doherty JJ; †SAGE Therapeutics, 215 First Street, Cambridge, Massachusetts 02142, United States.
  • Robichaud AJ; †SAGE Therapeutics, 215 First Street, Cambridge, Massachusetts 02142, United States.
J Med Chem ; 58(8): 3500-11, 2015 Apr 23.
Article in En | MEDLINE | ID: mdl-25799373
ABSTRACT
Neuroactive steroids (NASs) have been shown to impact central nervous system (CNS) function through positive allosteric modulation of the GABA(A) receptor (GABA(A)-R). Herein we report the effects on the activity and pharmacokinetic properties of a series of nor-19 pregnanolone analogues bearing a heterocyclic substituent at C-21. These efforts resulted in the identification of SGE-516, a balanced synaptic/extrasynaptic GABA(A) receptor modulator, and SGE-872, a selective extrasynaptic GABA(A) receptor modulator. Both molecules possess excellent druglike properties, making them advanced leads for oral delivery of GABA(A) receptor modulators.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pregnanolone / Receptors, GABA / Neurotransmitter Agents Limits: Animals / Humans Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2015 Document type: Article Affiliation country: Estados Unidos
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pregnanolone / Receptors, GABA / Neurotransmitter Agents Limits: Animals / Humans Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2015 Document type: Article Affiliation country: Estados Unidos