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. 2020 Jul 15;30(14):127214.
doi: 10.1016/j.bmcl.2020.127214. Epub 2020 Apr 25.

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

Andrew R Hudson  1 , Vincent J Santora  2 , Robert E Petroski  2 , Theresa A Almos  2 , Gary Anderson  2 , Richard Barido  2 , Jillian Basinger  2 , Chris L Bellows  2 , Brett C Bookser  2 , Nicola J Broadbent  2 , Clifford Cabebe  2 , Chih-Kun Chai  2 , Mi Chen  2 , Stephine Chow  2 , De Michael Chung  2 , Lindsay Heger  2 , Anne M Danks  2 , Graeme C Freestone  2 , Dany Gitnick  2 , Varsha Gupta  2 , Christine Hoffmaster  2 , Alan P Kaplan  2 , Michael R Kennedy  2 , Dong Lee  2 , James Limberis  2 , Kiev Ly  2 , Chi Ching Mak  2 , Brittany Masatsugu  2 , Andrew C Morse  2 , Jim Na  2 , David Neul  2 , John Nikpur  2 , Joel Renick  2 , Kristen Sebring  2 , Samantha Sevidal  2 , Ali Tabatabaei  2 , Jenny Wen  2 , Shouzhen Xia  2 , Yingzhuo Yan  2 , Zachary W Yoder  2 , Douglas Zook  2 , Marco Peters  2 , J Guy Breitenbucher  2
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Azetidine-based selective glycine transporter-1 (GlyT1) inhibitors with memory enhancing properties

Andrew R Hudson et al. Bioorg Med Chem Lett. .

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.

Keywords: Atropisomerism; GlyT1; Glycine; Occupancy; Rotamers.

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Conflict of interest statement

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.

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