Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1371510 | Bioorganic & Medicinal Chemistry Letters | 2012 | 5 Pages |
Abstract
Herein we describe the discovery and development of a novel class of M4 positive allosteric modulators, culminating in the discovery of ML293. ML293 exhibited modest potency at the human M4 receptor (EC50 = 1.3 μM) and excellent efficacy as noted by the 14.6-fold leftward shift of the agonist concentration–response curve. ML293 was also selective versus the other muscarinic subtypes and displayed excellent in vivo PK properties in rat with low IV clearance (11.6 mL/min/kg) and excellent brain exposure (PO PBL, 10 mg/kg at 1 h, [Brain] = 10.3 μM, B:P = 0.85).
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Related Topics
Physical Sciences and Engineering
Chemistry
Organic Chemistry
Authors
James M. Salovich, Paige N. Vinson, Douglas J. Sheffler, Atin Lamsal, Thomas J. Utley, Anna L. Blobaum, Thomas M. Bridges, Uyen Le, Carrie K. Jones, Michael R. Wood, J. Scott Daniels, P. Jeffrey Conn, Colleen M. Niswender, Craig W. Lindsley,