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Bioorg Med Chem Lett. 2015 Sep 15;25(18):3956-60. doi: 10.1016/j.bmcl.2015.07.031. Epub 2015 Jul 17.

Re-exploring the N-phenylpicolinamide derivatives to develop mGlu4 ligands with improved affinity and in vitro microsomal stability.

Author information

1
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, 149, 13th Street, Suite 2301, Charlestown, MA 02129, United States.
2
Department of Pharmacology, University of North Carolina Chapel Hill School of Medicine, Chapel Hill, NC 27514, United States.
3
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, 149, 13th Street, Suite 2301, Charlestown, MA 02129, United States. Electronic address: abrownell@partners.org.

Abstract

In recent years, mGlu4 has received great attention and research effort because of the potential benefits of mGlu4 activation in treating numerous brain disorders, such as Parkinson's disease (PD). Many positive allosteric modulators of mGlu4 have been developed. To better understand the role of mGlu4 in healthy and disease conditions, we are interested in developing an mGlu4 selective radioligand for in vivo studies. Thus, we had synthesized and studied [(11)C]2 as a PET tracer for mGlu4, which demonstrated some promising features as a PET radioligand as well as the limitation need to be improved. In order to develop an mGlu4 ligand with enhanced affinity and improved metabolic stability, we have modified, synthesized and evaluated a series of new N-phenylpicolinamide derivatives. The SAR study has discovered a number of compounds with low nM affinity to mGlu4. The dideuteriumfluoromethoxy modified compound 24 is identified as a very promising mGlu4 ligand, which has demonstrated enhanced affinity, improved in vitro microsomal stability, good selectivity and good permeability.

KEYWORDS:

Affinity; Metabolic stability; Metabotropic glutamate receptor subtype 4 (mGlu(4)); Positive allosteric modulator (PAM); Positron emission tomography (PET); Structure–affinity relationship (SAR)

PMID:
26231155
PMCID:
PMC4539532
DOI:
10.1016/j.bmcl.2015.07.031
[Indexed for MEDLINE]
Free PMC Article

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