SAR inspired by aldehyde oxidase (AO) metabolism: Discovery of novel, CNS penetrant tricyclic M4 PAMs

Trevor C Chopko; Changho Han; Alison R Gregro; Darren W Engers; Andrew S Felts; Mike S Poslusney; Katrina A Bollinger; Ryan D Morrison; Michael Bubser; Atin Lamsal; Vincent B Luscombe; Hyekyung P Cho; Nathalie C Schnetz-Boutaud; Alice L Rodriguez; Sichen Chang; J Scott Daniels; Donald F Stec; Colleen M Niswender; Carrie K Jones; Michael R Wood; Michael W Wood; Mark E Duggan; Nicholas J Brandon; P Jeffrey Conn; Thomas M Bridges; Craig W Lindsley; Bruce J Melancon

doi:10.1016/j.bmcl.2019.06.032

SAR inspired by aldehyde oxidase (AO) metabolism: Discovery of novel, CNS penetrant tricyclic M₄ PAMs

Bioorg Med Chem Lett. 2019 Aug 15;29(16):2224-2228. doi: 10.1016/j.bmcl.2019.06.032. Epub 2019 Jun 20.

Authors

Trevor C Chopko¹, Changho Han¹, Alison R Gregro¹, Darren W Engers², Andrew S Felts², Mike S Poslusney¹, Katrina A Bollinger¹, Ryan D Morrison¹, Michael Bubser², Atin Lamsal¹, Vincent B Luscombe¹, Hyekyung P Cho¹, Nathalie C Schnetz-Boutaud², Alice L Rodriguez², Sichen Chang², J Scott Daniels³, Donald F Stec⁴, Colleen M Niswender⁵, Carrie K Jones², Michael R Wood², Michael W Wood⁶, Mark E Duggan⁶, Nicholas J Brandon⁶, P Jeffrey Conn⁵, Thomas M Bridges², Craig W Lindsley⁷, Bruce J Melancon⁸

Affiliations

¹ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
² Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
³ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
⁴ Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
⁵ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, 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; Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
⁶ AstraZeneca Neuroscience, IMED Biotech Unit, R&D, Boston, MA 02451, USA.
⁷ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, 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; Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: craig.lindsley@vanderbilt.edu.
⁸ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: bruce.melancon@vanderbilt.edu.

Abstract

This letter describes progress towards an M₄ PAM preclinical candidate inspired by an unexpected aldehyde oxidase (AO) metabolite of a novel, CNS penetrant thieno[2,3-c]pyridine core to an equipotent, non-CNS penetrant thieno[2,3-c]pyrdin-7(6H)-one core. Medicinal chemistry design efforts yielded two novel tricyclic cores that enhanced M₄ PAM potency, regained CNS penetration, displayed favorable DMPK properties and afforded robust in vivo efficacy in reversing amphetamine-induced hyperlocomotion in rats.

Keywords: Aldehyde oxidase (AO); M(4); Muscarinic acetylcholine receptor; Positive allosteric modulator (PAM); Structure-activity relationship (SAR).

Publication types

Letter
Research Support, N.I.H., Extramural

MeSH terms

Aldehyde Oxidase / metabolism*
Animals
Drug Discovery
Humans
Myotonia Congenita / metabolism*
Rats
Receptor, Muscarinic M4 / metabolism*
Structure-Activity Relationship

SAR inspired by aldehyde oxidase (AO) metabolism: Discovery of novel, CNS penetrant tricyclic M₄ PAMs

Authors

Affiliations

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding