Azetidine-based selective glycine transporter-1 (GlyT1) inhibitors with memory enhancing properties.

Autor: Hudson AR; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States. Electronic address: andyrhudson@gmail.com., Santora VJ; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Petroski RE; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Almos TA; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Anderson G; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Barido R; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Basinger J; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Bellows CL; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Bookser BC; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Broadbent NJ; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Cabebe C; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Chai CK; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Chen M; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Chow S; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Chung M; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Heger L; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Danks AM; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Freestone GC; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Gitnick D; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Gupta V; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Hoffmaster C; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Kaplan AP; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Kennedy MR; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Lee D; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Limberis J; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Ly K; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Mak CC; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Masatsugu B; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Morse AC; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Na J; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Neul D; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Nikpur J; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Renick J; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Sebring K; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Sevidal S; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Tabatabaei A; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Wen J; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Xia S; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Yan Y; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Yoder ZW; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Zook D; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Peters M; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States., Breitenbucher JG; Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2020 Jul 15; Vol. 30 (14), pp. 127214. Date of Electronic Publication: 2020 Apr 25.
DOI: 10.1016/j.bmcl.2020.127214
Abstrakt: 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.)
Databáze: MEDLINE
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