Lead optimization of the VU0486321 series of mGlu1 PAMs. Part 1: SAR of modifications to the central aryl core.

Garcia-Barrantes PM, Cho HP, Blobaum AL, Niswender CM, Conn PJ, Lindsley CW
Bioorg Med Chem Lett. 2015 25 (22): 5107-10

PMID: 26476971 · PMCID: PMC4758672 · DOI:10.1016/j.bmcl.2015.10.013

This Letter describes the lead optimization of the VU0486321 series of mGlu1 positive allosteric modulators (PAMs). While first generation PAMs from Roche were reported in the late 1990s, little effort has focused on the development of mGlu1 PAMs since. New genetic data linking loss-of-function mutant mGlu1 receptors to schizophrenia, bipolar disorder and other neuropsychiatric disorders has rekindled interest in the target, but the ideal in vivo probe, for example, with good PK, brain penetration and low plasma protein binding, for robust target validation has been lacking. Here we describe the first modifications to the central aryl core of the VU0486321 series, where robust SAR was noted. Moreover, structural variants were identified that imparted selectivity (up to >793-fold) versus mGlu4.

Copyright © 2015 Elsevier Ltd. All rights reserved.

MeSH Terms (12)

Allosteric Regulation Animals Brain Coumarins Furans Humans Microsomes, Liver Phthalimides Rats Receptors, Metabotropic Glutamate Stereoisomerism Structure-Activity Relationship

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