Discovery and SAR of a novel series of metabotropic glutamate receptor 5 positive allosteric modulators with high ligand efficiency

Mark Turlington; Meredith J Noetzel; Thomas M Bridges; Paige N Vinson; Thomas Steckler; Hilde Lavreysen; Claire Mackie; José M Bartolomé-Nebreda; Susana Conde-Ceide; Han Min Tong; Gregor J Macdonald; J Scott Daniels; Carrie K Jones; Colleen M Niswender; P Jeffrey Conn; Craig W Lindsley; Shaun R Stauffer

doi:10.1016/j.bmcl.2014.04.087

Discovery and SAR of a novel series of metabotropic glutamate receptor 5 positive allosteric modulators with high ligand efficiency

Bioorg Med Chem Lett. 2014 Aug 1;24(15):3641-6. doi: 10.1016/j.bmcl.2014.04.087. Epub 2014 May 2.

Authors

Mark Turlington¹, Meredith J Noetzel², Thomas M Bridges², Paige N Vinson², Thomas Steckler³, Hilde Lavreysen³, Claire Mackie⁴, José M Bartolomé-Nebreda⁵, Susana Conde-Ceide⁵, Han Min Tong⁵, Gregor J Macdonald³, J Scott Daniels², Carrie K Jones², Colleen M Niswender², P Jeffrey Conn², Craig W Lindsley¹, Shaun R Stauffer⁶

Affiliations

¹ Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
² Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
³ Neuroscience, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
⁴ Discovery Sciences ADME/Tox, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
⁵ Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75, 45007 Toledo, Spain.
⁶ Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: shaun.stauffer@vanderbilt.edu.

Abstract

We report the optimization of a series of novel metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs) from a 5,6-bicyclic class of dihydropyrazolo[1,5-a]pyridin-4(5H)-ones containing a phenoxymethyl linker. Studies focused on a survey of non-amide containing hydrogen bond accepting (HBA) pharmacophore replacements. A highly potent and selective PAM, 2-(phenoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one (11, VU0462054), bearing a simple ketone moiety, was identified (LE=0.52, LELP=3.2). In addition, hydroxyl, difluoro, ether, and amino variations were examined. Despite promising lead properties and exploration of alternative core heterocycles, linkers, and ketone replacements, oxidative metabolism and in vivo clearance remained problematic for the series.

Keywords: Metabotropic glutamate receptor 5 (mGlu(5)); Positive allosteric modulator (PAM).

Publication types

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

MeSH terms

Allosteric Regulation / drug effects
Animals
Cell Line
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Ligands
Molecular Structure
Piperidones / chemical synthesis
Piperidones / chemistry
Piperidones / pharmacology*
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Rats
Receptor, Metabotropic Glutamate 5 / metabolism*
Structure-Activity Relationship

Substances

2-(phenoxymethyl)-6,7-dihydropyrazolo(1,5-a)pyridin-4(5H)-one
Ligands
Piperidones
Pyrazoles
Receptor, Metabotropic Glutamate 5

Abstract

Publication types

MeSH terms

Substances

Grants and funding