1. VU6005806/AZN-00016130, an advanced M4 positive allosteric modulator (PAM) profiled as a potential preclinical development candidate.
- Author
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Engers, Darren W., Melancon, Bruce J., Gregro, Allison R., Bertron, Jeanette L., Bollinger, Sean R., Felts, Andrew S., Konkol, Leah C., Wood, Michael R., Bollinger, Katrina A., Luscombe, Vincent B., Rodriguez, Alice L., Jones, Carrie K., Bubser, Michael, Yohn, Samantha E., Wood, Michael W., Brandon, Nicholas J., Dugan, Mark E., Niswender, Colleen M., Jeffrey Conn, P., and Bridges, Thomas M.
- Subjects
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MUSCARINIC acetylcholine receptors , *STRUCTURE-activity relationships , *DRUG solubility - Abstract
• First disclosure of VU6005806/AZN-00016130, an M 4 PAM profiled as a putative candidate. • Novel SAR findings based on novel variations to the C3 position on the pyridazine core. • Minimum effective dose of 0.56 mg/kg po in rat AHL. This letter describes progress towards an M 4 PAM preclinical candidate that resulted in the discovery of VU6005806/AZN-00016130. While the thieno[2,3- c ]pyridazine core has been a consistent feature of key M 4 PAMs, no work had previously been reported with respect to alternate functionality at the C3 position of the pyridazine ring. Here, we detail new chemistry and analogs that explored this region, and quickly led to VU6005806/AZN-00016130, which was profiled as a putative candidate. While, the β-amino carboxamide moiety engendered solubility limited absorption in higher species precluding advancement (or requiring extensive pharmaceutical sciences formulation), VU6005806/AZN-00016130 represents a new, high quality preclinical in vivo probe. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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