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

Darren W Engers; Bruce J Melancon; Allison R Gregro; Jeanette L Bertron; Sean R Bollinger; Andrew S Felts; Leah C Konkol; Michael R Wood; Katrina A Bollinger; Vincent B Luscombe; Alice L Rodriguez; Carrie K Jones; Michael Bubser; Samantha E Yohn; Michael W Wood; Nicholas J Brandon; Mark E Dugan; Colleen M Niswender; P Jeffrey Conn; Thomas M Bridges; Craig W Lindsley

doi:10.1016/j.bmcl.2019.05.026

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. Epub 2019 May 16.

Authors

Darren W Engers¹, Bruce J Melancon¹, Allison R Gregro¹, Jeanette L Bertron¹, Sean R Bollinger¹, Andrew S Felts¹, Leah C Konkol¹, Michael R Wood¹, Katrina A Bollinger¹, Vincent B Luscombe¹, Alice L Rodriguez¹, Carrie K Jones¹, Michael Bubser¹, Samantha E Yohn¹, Michael W Wood², Nicholas J Brandon², Mark E Dugan², Colleen M Niswender³, P Jeffrey Conn³, Thomas M Bridges⁴, Craig W Lindsley⁵

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).

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Regulation / immunology*
Molecular Structure
Receptor, Muscarinic M4 / immunology*
Structure-Activity Relationship

Substances

Receptor, Muscarinic M4

Grants and funding

U19 MH097056/MH/NIMH NIH HHS/United States