AI Article Synopsis
- - A series of triazolopyridine ethers were developed that act as positive allosteric modulators (PAMs) for mGlu, leading to the identification of a promising compound, BMT-133218, with effective brain penetration and selectivity.
- - In animal studies, BMT-133218 successfully reversed locomotor activity stimulated by PCP and prevented memory deficits induced by MK-801, showing potential benefits in cognitive functions.
- - The compound demonstrated high lipophilicity and extensive plasma protein binding, which affected its efficacy at lower doses, highlighting the need for further research on its use as a treatment for schizophrenia.
Article Abstract
Triazolopyridine ethers with mGlu 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 mGlu PAMs for the treatment of schizophrenia and merit further preclinical investigation.
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| http://dx.doi.org/10.1016/j.bmc.2016.11.018 | DOI Listing |
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