Discovery of a novel, CNS penetrant M4 PAM chemotype based on a 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core

Blake R Bewley; Paul K Spearing; Rebecca L Weiner; Vincent B Luscombe; Xiaoyan Zhan; Sichen Chang; Hyekyung P Cho; Alice L Rodriguez; Colleen M Niswender; P Jeffrey Conn; Thomas M Bridges; Darren W Engers; Craig W Lindsley

doi:10.1016/j.bmcl.2017.08.043

Discovery of a novel, CNS penetrant M₄ PAM chemotype based on a 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core

Bioorg Med Chem Lett. 2017 Sep 15;27(18):4274-4279. doi: 10.1016/j.bmcl.2017.08.043. Epub 2017 Aug 20.

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; Vanderbilt Kennedy Center, 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.
⁴ 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: darren.engers@vanderbilt.edu.
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; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: craig.lindsley@vanderbilt.edu.

Abstract

This Letter details the discovery and subsequent optimization of a novel M₄ PAM scaffold based on an 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core, which represents a distinct departure from the classical M₄ PAM chemotypes. Optimized compounds in this series demonstrated improved M₄ PAM potency on both human and rat M₄ (4 to 5-fold relative to HTS hit), and displayed attractive physicochemical and DMPK profiles, including good CNS penetration (rat brain:plasma K_p=5.3, K_p,uu=2.4; MDCK-MDR1 (P-gp) ER=1.1).

Keywords: M(4); Muscarinic acetylcholine receptor; Non-human primate (NHP); 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

Animals
Central Nervous System / drug effects*
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Molecular Structure
Piperidines / chemical synthesis
Piperidines / chemistry
Piperidines / pharmacology*
Quinolines / chemical synthesis
Quinolines / chemistry
Quinolines / pharmacology*
Rats
Receptor, Muscarinic M4 / antagonists & inhibitors*
Structure-Activity Relationship

Substances

6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile
Piperidines
Quinolines
Receptor, Muscarinic M4