1. Triazolopyridine ethers as potent, orally active mGlu 2 positive allosteric modulators for treating schizophrenia.
- Author
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Higgins MA, Marcin LR, Christopher Zusi F, Gentles R, Ding M, Pearce BC, Easton A, Kostich WA, Seager MA, Bourin C, Bristow LJ, Johnson KA, Miller R, Hogan J, Whiterock V, Gulianello M, Ferrante M, Huang Y, Hendricson A, Alt A, Macor JE, and Bronson JJ
- Subjects
- Administration, Oral, Allosteric Regulation drug effects, Animals, Disease Models, Animal, Dose-Response Relationship, Drug, Ethers administration & dosage, Ethers chemistry, Haplorhini, Male, Mice, Mice, Inbred C57BL, Models, Molecular, Molecular Structure, Pyridines administration & dosage, Pyridines chemistry, Rats, Rats, Sprague-Dawley, Receptors, Metabotropic Glutamate metabolism, Schizophrenia metabolism, Structure-Activity Relationship, Triazoles administration & dosage, Triazoles chemistry, Ethers pharmacology, Pyridines pharmacology, Receptors, Metabotropic Glutamate antagonists & inhibitors, Schizophrenia drug therapy, Triazoles pharmacology
- Abstract
Triazolopyridine ethers with mGlu
2 positive allosteric modulator (PAM) activity are disclosed. The synthesis, in vitro activity, and metabolic stability data for a series of analogs is provided. The effort resulted in the discovery of a potent, selective, and brain penetrant lead molecule BMT-133218 ((+)-7m). After oral administration at 10mg/kg, BMT-133218 demonstrated full reversal of PCP-stimulated locomotor activity and prevented MK-801-induced working memory deficits in separate mouse models. Also, reversal of impairments in executive function were observed in rat set-shifting studies at 3 and 10mg/kg (p.o.). Extensive plasma protein binding as the result of high lipophilicity likely limited activity at lower doses. Optimized triazolopyridine ethers offer utility as mGlu2 PAMs for the treatment of schizophrenia and merit further preclinical investigation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)- Published
- 2017
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