2. Academic Validation
  3. 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)

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.
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

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 CLp = 3.1 mL/min/kg, t1/2 = 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.

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