Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1370051 | Bioorganic & Medicinal Chemistry Letters | 2016 | 6 Pages |
Abstract
This Letter describes the further lead optimization of the VU0486321 series of mGlu1 positive allosteric modulators (PAMs), driven by recent genetic data linking loss of function GRM1 to schizophrenia. Steep and caveat-laden SAR plagues the series, but ultimately potent mGlu1 PAMs (EC50s ∼5 nM) have resulted with good DMPK properties (low intrinsic clearance, clean CYP profile, modest Fu) and CNS penetration (Kps 0.25–0.97), along with up to >450-fold selectivity versus mGlu4 and mGlu5.
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Physical Sciences and Engineering
Chemistry
Organic Chemistry
Authors
Pedro M. Garcia-Barrantes, Hyekyung P. Cho, Adam M. Metts, Anna L. Blobaum, Colleen M. Niswender, P. Jeffrey Conn, Craig W. Lindsley,