1. Azetidine-based selective glycine transporter-1 (GlyT1) inhibitors with memory enhancing properties.
- Author
-
Hudson AR, Santora VJ, Petroski RE, Almos TA, Anderson G, Barido R, Basinger J, Bellows CL, Bookser BC, Broadbent NJ, Cabebe C, Chai CK, Chen M, Chow S, Chung M, Heger L, Danks AM, Freestone GC, Gitnick D, Gupta V, Hoffmaster C, Kaplan AP, Kennedy MR, Lee D, Limberis J, Ly K, Mak CC, Masatsugu B, Morse AC, Na J, Neul D, Nikpur J, Renick J, Sebring K, Sevidal S, Tabatabaei A, Wen J, Xia S, Yan Y, Yoder ZW, Zook D, Peters M, and Breitenbucher JG
- Subjects
- Azetidines chemical synthesis, Azetidines chemistry, Dose-Response Relationship, Drug, HEK293 Cells, Humans, Molecular Structure, Structure-Activity Relationship, Azetidines pharmacology, Glycine Plasma Membrane Transport Proteins antagonists & inhibitors, Memory drug effects
- Abstract
A strategy to conformationally restrain a series of GlyT1 inhibitors identified potent analogs that exhibited slowly interconverting rotational isomers. Further studies to address this concern led to a series of azetidine-based inhibitors. Compound 26 was able to elevate CSF glycine levels in vivo and demonstrated potency comparable to Bitopertin in an in vivo rat receptor occupancy study. Compound 26 was subsequently shown to enhance memory in a Novel Object Recognition (NOR) behavioral study after a single dose of 0.03 mg/kg, and in a contextual fear conditioning (cFC) study after four QD doses of 0.01-0.03 mg/kg., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF