The discovery of VU0486846: steep SAR from a series of M1 PAMs based on a novel benzomorpholine core

Jeanette L Bertron; Hyekyung P Cho; Pedro M Garcia-Barrantes; Joseph D Panarese; James M Salovich; Kellie D Nance; Darren W Engers; Jerri M Rook; Anna L Blobaum; Colleen M Niswender; Shaun R Stauffer; P Jeffrey Conn; Craig W Lindsley

doi:10.1016/j.bmcl.2018.05.009

The discovery of VU0486846: steep SAR from a series of M₁ PAMs based on a novel benzomorpholine core

Bioorg Med Chem Lett. 2018 Jul 1;28(12):2175-2179. doi: 10.1016/j.bmcl.2018.05.009. Epub 2018 May 5.

Affiliations

¹ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
² 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.
³ 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.
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; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
⁵ 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; Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: craig.lindsley@vanderbilt.edu.

Abstract

This letter describes the chemical optimization of a new series of M₁ positive allosteric modulators (PAMs) based on a novel benzomorpholine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0486846 (7), devoid of adverse effect liability. This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0486846 and details all of the challenges faced in allosteric modulator programs (both steep and flat SAR, as well as subtle structural changes affecting CNS penetration and overall physiochemical and DMPK properties).

Keywords: M(1); Muscarinic acetylcholine receptor; Positive allosteric modulator (PAM); Schizophrenia; Structure-Activity Relationship (SAR).

Publication types

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

MeSH terms

Animals
CHO Cells
Cricetulus
Drug Discovery*
Humans
Molecular Structure
Morpholines / chemical synthesis
Morpholines / chemistry
Morpholines / pharmacology*
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Rats
Receptor, Muscarinic M1 / agonists*
Structure-Activity Relationship

Substances

Morpholines
Pyrazoles
Receptor, Muscarinic M1
VU0486846