| Literature DB >> 29886732 |
Vincent J Santora1, Theresa A Almos1, Richard Barido1, Jillian Basinger1, Chris L Bellows1, Brett C Bookser1, J Guy Breitenbucher1, Nicola J Broadbent1, Clifford Cabebe1, Chih-Kun Chai1, Mi Chen1, Stephine Chow1, De Michael Chung1, Lindsay Crickard1, Anne M Danks1, Graeme C Freestone1, Dany Gitnick1, Varsha Gupta1, Christine Hoffmaster1, Andrew R Hudson1, Alan P Kaplan1, Michael R Kennedy1, Dong Lee1, James Limberis1, Kiev Ly1, Chi Ching Mak1, Brittany Masatsugu1, Andrew C Morse1, Jim Na1, David Neul1, John Nikpur1, Marco Peters1, Robert E Petroski1, Joel Renick1, Kristen Sebring1, Samantha Sevidal1, Ali Tabatabaei1, Jenny Wen1, Yingzhuo Yan1, Zachary W Yoder1, Douglas Zook1.
Abstract
We report here the identification and optimization of a novel series of potent GlyT1 inhibitors. A ligand design campaign that utilized known GlyT1 inhibitors as starting points led to the identification of a novel series of pyrrolo[3,4- c]pyrazoles amides (21-50) with good in vitro potency. Subsequent optimization of physicochemical and in vitro ADME properties produced several compounds with promising pharmacokinetic profiles. In vivo inhibition of GlyT1 was demonstrated for select compounds within this series by measuring the elevation of glycine in the cerebrospinal fluid (CSF) of rats after a single oral dose of 10 mg/kg. Ultimately, an optimized lead, compound 46, demonstrated in vivo efficacy in a rat novel object recognition (NOR) assay after oral dosing at 0.1, 1, and 3 mg/kg.Entities:
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Year: 2018 PMID： 29886732 DOI： 10.1021/acs.jmedchem.8b00372
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446