2. Academic Validation
  3. VU6005806/AZN-00016130, an advanced M4 positive allosteric modulator (PAM) profiled as a potential preclinical development candidate

VU6005806/AZN-00016130, an advanced M4 positive allosteric modulator (PAM) profiled as a potential preclinical development candidate

  • Bioorg Med Chem Lett. 2019 Jul 15;29(14):1714-1718. doi: 10.1016/j.bmcl.2019.05.026.
Darren W Engers 1,  Bruce J Melancon 1,  Allison R Gregro 1,  Jeanette L Bertron 1,  Sean R Bollinger 1,  Andrew S Felts 1,  Leah C Konkol 1,  Michael R Wood 1,  Katrina A Bollinger 1,  Vincent B Luscombe 1,  Alice L Rodriguez 1,  Carrie K Jones 1,  Michael Bubser 1,  Samantha E Yohn 1,  Michael W Wood 2,  Nicholas J Brandon 2,  Mark E Dugan 2,  Colleen M Niswender 3,  P Jeffrey Conn 3,  Thomas M Bridges 4,  Craig W Lindsley 5
Affiliations

Affiliations

  • 1 Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 2 AstraZeneca Neuroscience, IMED Biotech Unit, R&D Boston, MA 02451, USA.
  • 3 Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 4 Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: thomas.m.bridges@vanderbilt.edu.
  • 5 Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: craig.lindsley@vanderbilt.edu.
PMID: 31113706 DOI: 10.1016/j.bmcl.2019.05.026
Abstract

This letter describes progress towards an M4 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.

Keywords

M(4); Muscarinic acetylcholine receptor; Pharmacokinetics; Positive allosteric modulator (PAM); Structure-activity relationship (SAR).

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