Design and Synthesis of Novel and Selective Glycine Transporter-1 (GlyT1) Inhibitors with Memory Enhancing Properties.

Autor:	Santora VJ; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Almos TA; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Barido R; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Basinger J; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Bellows CL; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Bookser BC; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Breitenbucher JG; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Broadbent NJ; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Cabebe C; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Chai CK; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Chen M; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Chow S; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Chung M; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Crickard L; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Danks AM; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Freestone GC; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Gitnick D; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Gupta V; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Hoffmaster C; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Hudson AR; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Kaplan AP; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Kennedy MR; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Lee D; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Limberis J; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Ly K; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Mak CC; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Masatsugu B; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Morse AC; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Na J; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Neul D; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Nikpur J; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Peters M; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Petroski RE; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Renick J; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Sebring K; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Sevidal S; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Tabatabaei A; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Wen J; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Yan Y; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Yoder ZW; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States., Zook D; Dart NeuroScience LLC , 12278 Scripps Summit Drive , San Diego , California 92121 , United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2018 Jul 26; Vol. 61 (14), pp. 6018-6033. Date of Electronic Publication: 2018 Jul 11.
DOI:	10.1021/acs.jmedchem.8b00372
Abstrakt:	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.
Databáze:	MEDLINE
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