Lead optimization of the VU0486321 series of mGlu1 PAMs. Part 3. Engineering plasma stability by discovery and optimization of isoindolinone analogs.

Garcia-Barrantes PM, Cho HP, Blobaum AL, Niswender CM, Conn PJ, Lindsley CW
Bioorg Med Chem Lett. 2016 26 (8): 1869-72

PMID: 26988302 · PMCID: PMC4823774 · DOI:10.1016/j.bmcl.2016.03.031

This Letter describes the further lead optimization of the VU0486321 series of mGlu1 positive allosteric modulators (PAMs), focused on addressing the recurrent issue of plasma instability of the phthalimide moiety. Here, we evaluated a number of phthalimide bioisosteres, and ultimately identified isoindolinones as the ideal replacement that effectively address plasma instability, while maintaining acceptable mGlu1 PAM potency, DMPK profile, CNS penetration and mGluR selectivity.

Copyright © 2016 Elsevier Ltd. All rights reserved.

MeSH Terms (14)

Allosteric Regulation Central Nervous System Coumarins Dose-Response Relationship, Drug Drug Discovery Drug Stability Furans Humans Isoindoles Molecular Structure Phthalimides Receptors, Metabotropic Glutamate Structure-Activity Relationship Substrate Specificity

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