The discovery of VU0652957 (VU2957, Valiglurax): SAR and DMPK challenges en route to an mGlu PAM development candidate.

Panarese JD, Engers DW, Wu YJ, Guernon JM, Chun A, Gregro AR, Bender AM, Capstick RA, Wieting JM, Bronson JJ, Macor JE, Westphal R, Soars M, Engers JE, Felts AS, Rodriguez AL, Emmitte KA, Jones CK, Blobaum AL, Conn PJ, Niswender CM, Hopkins CR, Lindsley CW
Bioorg Med Chem Lett. 2019 29 (2): 342-346

PMID: 30503632 · DOI:10.1016/j.bmcl.2018.10.050

This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu positive allosteric modulators (PAMs), leading to the identification of VU0652957 (VU2957, Valiglurax), a compound profiled as a preclinical development candidate. Here, we detail the challenges faced in allosteric modulator programs (e.g., steep SAR, as well as subtle structural changes affecting overall physiochemical/DMPK properties and CNS penetration).

Copyright © 2018 Elsevier Ltd. All rights reserved.

MeSH Terms (10)

Allosteric Regulation Dose-Response Relationship, Drug Drug Discovery Heterocyclic Compounds, 2-Ring Humans Isoquinolines Molecular Structure Myotonin-Protein Kinase Receptors, Metabotropic Glutamate Structure-Activity Relationship

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