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. 2011 Jun 1;21(11):3243-7.
doi: 10.1016/j.bmcl.2011.04.047. Epub 2011 Apr 20.

Potent mGluR5 antagonists: pyridyl and thiazolyl-ethynyl-3,5-disubstituted-phenyl series

David Alagille  1 , Herve DaCosta, Yelin Chen, Kamondanai Hemstapat, Alice Rodriguez, Ronald M Baldwin, P Jeffrey Conn, Gilles D Tamagnan
Affiliations

Potent mGluR5 antagonists: pyridyl and thiazolyl-ethynyl-3,5-disubstituted-phenyl series

David Alagille et al. Bioorg Med Chem Lett. .

Erratum in

  • Bioorg Med Chem Lett. 2012 Mar 1;22(5):2130. Conn, Jeffrey P [corrected to Conn, P Jeffrey]

Abstract

We report the synthesis of four series of 3,5-disubstituted-phenyl ligands targeting the metabotropic glutamate receptor subtype 5: (2-methylthiazol-4-yl)ethynyl (1a-j,), (6-methylpyridin-2-yl)ethynyl (2a-j), (5-methylpyridin-2-yl)ethynyl (3a-j,), and (pyridin-2-yl)ethynyl (4a-j,). The compounds were evaluated for antagonism of glutamate-mediated mobilization of internal calcium in an mGluR5 in vitro assay. All compounds were found to be full antagonists and exhibited low nanomolar to subnanomolar activity.

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Figures

Figure 1
Figure 1
Selected mGluR5 antagonists described in the literature.
Scheme 1
Scheme 1
Synthesis of compounds 1, 2, 3, and 4. Reagents and conditions: (a) trimethylsilylacetylene, PdCl2(PPh3)2, Et3N; (b) 9a–j, PdCl2(PPh3)2, Et3N, TBAF, DMF, 60 °C or rt; (c) see Ref. 20.
Scheme 2
Scheme 2
Synthesis of compounds 9a–h. Reagents and conditions: (a) (i) SOCl2, reflux, (ii) NH4OH; (b) SOCl2, reflux; (c) Br2, AcOH, 50 °C; (d) isoamyl nitrite, DMF, 50 °C.
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