1. VU6005806/AZN-00016130, an advanced M 4 positive allosteric modulator (PAM) profiled as a potential preclinical development candidate.
- Author
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Engers DW, Melancon BJ, Gregro AR, Bertron JL, Bollinger SR, Felts AS, Konkol LC, Wood MR, Bollinger KA, Luscombe VB, Rodriguez AL, Jones CK, Bubser M, Yohn SE, Wood MW, Brandon NJ, Dugan ME, Niswender CM, Conn PJ, Bridges TM, and Lindsley CW
- Subjects
- Molecular Structure, Structure-Activity Relationship, Allosteric Regulation immunology, Receptor, Muscarinic M4 immunology
- Abstract
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 M4 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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)- Published
- 2019
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