Discovery of imidazo[1,2-a]-, [1,2,4]triazolo[4,3-a]-, and [1,2,4]triazolo[1,5-a]pyridine-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5

Andrew S Felts; Alice L Rodriguez; Ryan D Morrison; Katrina A Bollinger; Daryl F Venable; Anna L Blobaum; Frank W Byers; Analisa Thompson Gray; J Scott Daniels; Colleen M Niswender; Carrie K Jones; P Jeffrey Conn; Craig W Lindsley; Kyle A Emmitte

doi:10.1016/j.bmcl.2017.09.042

Discovery of imidazo[1,2-a]-, [1,2,4]triazolo[4,3-a]-, and [1,2,4]triazolo[1,5-a]pyridine-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5

Bioorg Med Chem Lett. 2017 Nov 1;27(21):4858-4866. doi: 10.1016/j.bmcl.2017.09.042. Epub 2017 Sep 20.

Affiliations

¹ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
² Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University Medical Center, TN 37232, USA.
³ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
⁴ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: kyle.emmitte@unthsc.edu.

Abstract

Based on a hypothesis that an intramolecular hydrogen bond was present in our lead series of picolinamide mGlu₅ NAMs, we reasoned that an inactive nicotinamide series could be modified through introduction of a fused heterocyclic core to generate potent mGlu₅ NAMs. In this Letter, we describe the synthesis and evaluation of compounds that demonstrate the viability of that approach. Selected analogs were profiled in a variety of in vitro assays, and two compounds were evaluated in rat pharmacokinetic studies and a mouse model of obsessive-compulsive disorder. Ancillary pharmacology screening revealed that members of this series exhibited moderate inhibition of the dopamine transporter (DAT), and SAR was developed that expanded the selectivity for mGlu₅ versus DAT.

Keywords: Central nervous system (CNS); G-protein coupled receptor (GPCR); Heterocycle; Metabotropic glutamate receptor subtype 5 (mGlu(5)); Negative allosteric modulator (NAM).

Publication types

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

MeSH terms

Allosteric Regulation
Amides / chemistry*
Amides / pharmacokinetics
Amides / pharmacology
Animals
Cell Membrane Permeability / drug effects
Dogs
Dopamine Plasma Membrane Transport Proteins / antagonists & inhibitors
Dopamine Plasma Membrane Transport Proteins / metabolism
Drug Evaluation, Preclinical
Half-Life
Humans
Inhibitory Concentration 50
Madin Darby Canine Kidney Cells
Mice
Microsomes, Liver / metabolism
Pyridines / chemistry
Rats
Receptor, Metabotropic Glutamate 5 / chemistry
Receptor, Metabotropic Glutamate 5 / metabolism*
Structure-Activity Relationship
Triazoles / chemistry

Substances

Amides
Dopamine Plasma Membrane Transport Proteins
Pyridines
Receptor, Metabotropic Glutamate 5
Triazoles
imidazo(1,2-a)pyridine

Discovery of imidazo[1,2-a]-, [1,2,4]triazolo[4,3-a]-, and [1,2,4]triazolo[1,5-a]pyridine-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5

Authors

Affiliations

Abstract

Publication types

MeSH terms

Substances

Grants and funding