Further optimization of the mGIu5 PAM clinical candidate VU0409551/JNJ-46778212: Progress and challenges towards a back-up compound

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:25

Article

Zhou, Ya^1,2  Malosh, Chrysa^1,2  Conde-Ceide, Susana³  Manuel Martinez-Viturro, Carlos³  Alcazar, Jesus³  Lavreysen, Hilde⁴  Mackie, Claire⁵  Bridges, Thomas M.^1,2  Daniels, J. Scott^1,2  Niswender, Colleen M.^1,2  Jones, Carrie K.^1,2  Macdonald, Gregor J.⁴  Steckler, Thomas⁴  Conn, P. Jeffrey^1,2  Stauffer, Shaun R.^1,2  Manuel Bartolome-Nebreda, Jose³  Lindsley, Craig W.^1,2 

[1] Vanderbilt Univ Sch Med, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA

[2] Vanderbilt Univ Sch Med, Dept Pharmacol, Nashville, TN 37232 USA

[3] Janssen Res & Dev, Neurosci Med Chem, Toledo 45007, Spain

[4] Janssen Res & Dev, Neurosci, B-2340 Beerse, Belgium

[5] Janssen Res & Dev, Discovery Sci ADME Tox, B-2340 Beerse, Belgium

关键词: mGlu(5);    Metabotropic glutamate receptor;    Positive allosteric modulator (PAM);    Pharmacokinetics;    Schizophrenia;   

DOI  :  10.1016/j.bmcl.2015.06.096

来源: Elsevier

【 摘 要 】

This Letter describes the progress and challenges in the continued optimization of the mGlu(5) positive allosteric modulator (PAM) clinical candidate VU0490551/JNJ-46778212. While many analogs addressed key areas for improvement, no one compound possessed the amalgamation of improvements needed within the (2(phenoxymethyl)-6,7-dihydrooxazolo[5,4-c] pyridine-5(4H)-yl(aryl) methanone scaffold to advance as a back-up clinical candidate. However, many analogs displayed excellent solubility and physiochemical properties, and were active in the amphetamine-induced hyperlocomotion (AHL) model. Moreover, the SAR was robust for this series of PAMs, and both polar and hydrogen-bond donors were found to be tolerated, leading to analogs with overall attractive profiles and good ligand efficiencies. (C) 2015 Elsevier Ltd. All rights reserved.

【 授权许可】

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