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
  • 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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