Optimization of M4 positive allosteric modulators (PAMs): The discovery of VU0476406, a non-human primate in vivo tool compound for translational pharmacology

Bruce J Melancon; Michael R Wood; Meredith J Noetzel; Kellie D Nance; Eileen M Engelberg; Changho Han; Atin Lamsal; Sichen Chang; Hyekyung P Cho; Frank W Byers; Michael Bubser; Carrie K Jones; Colleen M Niswender; Michael W Wood; Darren W Engers; Dedong Wu; Nicholas J Brandon; Mark E Duggan; P Jeffrey Conn; Thomas M Bridges; Craig W Lindsley

doi:10.1016/j.bmcl.2017.04.043

Optimization of M₄ positive allosteric modulators (PAMs): The discovery of VU0476406, a non-human primate in vivo tool compound for translational pharmacology

Bioorg Med Chem Lett. 2017 Jun 1;27(11):2296-2301. doi: 10.1016/j.bmcl.2017.04.043. Epub 2017 Apr 13.

Authors

Bruce J Melancon¹, Michael R Wood², Meredith J Noetzel¹, Kellie D Nance³, Eileen M Engelberg³, Changho Han³, Atin Lamsal³, Sichen Chang³, Hyekyung P Cho¹, Frank W Byers³, Michael Bubser³, Carrie K Jones⁴, Colleen M Niswender⁴, Michael W Wood⁵, Darren W Engers¹, Dedong Wu⁶, Nicholas J Brandon⁵, Mark E Duggan⁵, P Jeffrey Conn⁴, Thomas M Bridges⁷, Craig W Lindsley⁸

Affiliations

¹ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
² Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
³ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
⁴ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, 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.
⁵ AstraZeneca, Neuroscience, Innovative Medicines & Early Development, Waltham, MA 02451, USA.
⁶ AstraZeneca, Pharmaceutical Science, 35 Gatehouse Drive, Waltham, MA 02451, USA.
⁷ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: thomas.m.bridges@vanderbilt.edu.
⁸ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, 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. Electronic address: craig.lindsley@vanderbilt.edu.

Abstract

This letter describes the further chemical optimization of the 5-amino-thieno[2,3-c]pyridazine series (VU0467154/VU0467485) of M₄ positive allosteric modulators (PAMs), developed via iterative parallel synthesis, culminating in the discovery of the non-human primate (NHP) in vivo tool compound, VU0476406 (8p). VU0476406 is an important in vivo tool compound to enable translation of pharmacodynamics from rodent to NHP, and while data related to a Parkinson's disease model has been reported with 8p, this is the first disclosure of the optimization and discovery of VU0476406, as well as detailed pharmacology and DMPK properties.

Keywords: M(4); Muscarinic acetylcholine receptor; Non-human primate (NHP); Positive allosteric modulator (PAM); Structure-Activity Relationship (SAR).

MeSH terms

Allosteric Regulation
Animals
Crystallography, X-Ray
Drug Discovery*
Hydrogen Bonding
Pyridazines / chemistry
Pyridazines / pharmacology*
Rats
Structure-Activity Relationship
Thiophenes / chemistry
Thiophenes / pharmacology*
Translational Research, Biomedical*

Substances

Pyridazines
Thiophenes
VU0476406

Abstract

MeSH terms

Substances

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