Challenges in the development of an M4 PAM preclinical candidate: The discovery, SAR, and in vivo characterization of a series of 3-aminoazetidine-derived amides

James C Tarr; Michael R Wood; Meredith J Noetzel; Jeanette L Bertron; Rebecca L Weiner; Alice L Rodriguez; Atin Lamsal; Frank W Byers; Sichen Chang; Hyekyung P Cho; Carrie K Jones; Colleen M Niswender; Michael W Wood; Nicholas J Brandon; Mark E Duggan; P Jeffrey Conn; Thomas M Bridges; Craig W Lindsley

doi:10.1016/j.bmcl.2017.05.014

Challenges in the development of an M₄ PAM preclinical candidate: The discovery, SAR, and in vivo characterization of a series of 3-aminoazetidine-derived amides

Bioorg Med Chem Lett. 2017 Jul 1;27(13):2990-2995. doi: 10.1016/j.bmcl.2017.05.014. Epub 2017 May 6.

Authors

James C Tarr¹, Michael R Wood², Meredith J Noetzel³, Jeanette L Bertron¹, Rebecca L Weiner¹, Alice L Rodriguez¹, Atin Lamsal¹, Frank W Byers³, Sichen Chang³, Hyekyung P Cho¹, Carrie K Jones⁴, Colleen M Niswender⁴, Michael W Wood⁵, Nicholas J Brandon⁵, Mark E Duggan⁵, P Jeffrey Conn⁴, Thomas M Bridges⁶, Craig W Lindsley⁷

Affiliations

¹ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
² Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, 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.
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; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
⁵ Neuroscience Innovative Medicines, Astra Zeneca, 141 Portland Street, Cambridge, MA 02139, USA.
⁶ 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.
⁷ 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. Electronic address: craig.lindsley@vanderbilt.edu.

Abstract

This letter details the continued chemical optimization of a novel series of M₄ positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core by incorporating a 3-amino azetidine amide moiety. The analogs described within this work represent the most potent M₄ PAMs reported for this series to date. The SAR to address potency, clearance, subtype selectivity, CNS exposure, and P-gp efflux are described. This work culminated in the discovery of VU6000918, which demonstrated robust efficacy in a rat amphetamine-induced hyperlocomotion reversal model at a minimum efficacious dose of 0.3mg/kg.

Keywords: Azetidine; M(4); Muscarinic acetylcholine receptor; Positive allosteric modulator (PAM); Schizophrenia.

Publication types

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

MeSH terms

Allosteric Regulation / drug effects
Amides / chemical synthesis
Amides / chemistry
Amides / pharmacology*
Animals
Azetidines / chemical synthesis
Azetidines / chemistry
Azetidines / pharmacology*
Disease Models, Animal
Dose-Response Relationship, Drug
Humans
Molecular Structure
Rats
Receptor, Muscarinic M4 / antagonists & inhibitors*
Structure-Activity Relationship

Substances

Amides
Azetidines
Receptor, Muscarinic M4

Abstract

Publication types

MeSH terms

Substances

Grants and funding