Discovery, Structure-Activity Relationship, and Biological Characterization of a Novel Series of 6-((1 H-Pyrazolo[4,3- b]pyridin-3-yl)amino)-benzo[ d]isothiazole-3-carboxamides as Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 4 (mGlu4)

Sean R Bollinger; Darren W Engers; Joseph D Panarese; Mary West; Julie L Engers; Matthew T Loch; Alice L Rodriguez; Anna L Blobaum; Carrie K Jones; Analisa Thompson Gray; P Jeffrey Conn; Craig W Lindsley; Colleen M Niswender; Corey R Hopkins

doi:10.1021/acs.jmedchem.8b00994

Discovery, Structure-Activity Relationship, and Biological Characterization of a Novel Series of 6-((1 H-Pyrazolo[4,3- b]pyridin-3-yl)amino)-benzo[ d]isothiazole-3-carboxamides as Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 4 (mGlu₄)

J Med Chem. 2019 Jan 10;62(1):342-358. doi: 10.1021/acs.jmedchem.8b00994. Epub 2018 Oct 10.

Authors

Sean R Bollinger^{1

2}, Darren W Engers^{1

2}, Joseph D Panarese^{1

2}, Mary West^{1

2}, Julie L Engers^{1

2}, Matthew T Loch^{1

2}, Alice L Rodriguez^{1

2}, Anna L Blobaum^{1

2}, Carrie K Jones^{1

2}, Analisa Thompson Gray^{1

2}, P Jeffrey Conn^{1

2

3}, Craig W Lindsley^{1

2

4

5}, Colleen M Niswender^{1

2

3}, Corey R Hopkins^{1

2

4}

Affiliations

¹ Vanderbilt Center for Neuroscience Drug Discovery , Vanderbilt University , Nashville , Tennessee 37232 , United States.
² Department of Pharmacology , Vanderbilt University , Nashville , Tennessee 37232 , United States.
³ Vanderbilt Kennedy Center , Vanderbilt University Medical Center , Nashville , Tennessee 37232 , United States.
⁴ Department of Chemistry , Vanderbilt University , Nashville , Tennessee 37232 , United States.
⁵ Department of Biochemistry , Vanderbilt University , Nashville , Tennessee 37232 , United States.

PMID: 30247901
DOI: 10.1021/acs.jmedchem.8b00994

Abstract

This work describes the discovery and characterization of novel 6-(1 H-pyrazolo[4,3- b]pyridin-3-yl)amino-benzo[ d]isothiazole-3-carboxamides as mGlu₄ PAMs. This scaffold provides improved metabolic clearance and CYP1A2 profiles compared to previously discovered mGlu₄ PAMs. From this work, 27o (VU6001376) was identified as a potent (EC₅₀ = 50.1 nM, 50.5% GluMax) and selective mGlu₄ PAM with an excellent rat DMPK profile ( in vivo rat CL_p = 3.1 mL/min/kg, t_1/2 = 445 min, CYP1A2 IC₅₀ > 30 μM). Compound 27o was also active in reversing haloperidol induced catalepsy in a rodent preclinical model of Parkinson's disease.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Regulation
Amides / chemistry*
Amides / metabolism
Amides / pharmacokinetics
Amides / therapeutic use
Animals
Brain / metabolism
Catalepsy / chemically induced
Catalepsy / drug therapy
Catalepsy / pathology
Cytochrome P-450 CYP1A2 / metabolism
Half-Life
Haloperidol / toxicity
Humans
Isoxazoles / chemistry
Male
Rats
Rats, Sprague-Dawley
Receptors, Metabotropic Glutamate / chemistry*
Receptors, Metabotropic Glutamate / metabolism
Structure-Activity Relationship

Substances

Amides
Isoxazoles
Receptors, Metabotropic Glutamate
Cytochrome P-450 CYP1A2
Haloperidol
metabotropic glutamate receptor 4