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. 2016 Jul 1;26(13):2984-2987.
doi: 10.1016/j.bmcl.2016.05.029. Epub 2016 May 11.

Discovery and characterization of a novel series of N-phenylsulfonyl-1H-pyrrole picolinamides as positive allosteric modulators of the metabotropic glutamate receptor 4 (mGlu4)

Rocco D Gogliotti  1 , Anna L Blobaum  1 , Ryan M Morrison  1 , J Scott Daniels  1 , James M Salovich  1 , Yiu-Yin Cheung  1 , Alice L Rodriguez  1 , Matthew T Loch  1 , P Jeffrey Conn  2 , Craig W Lindsley  3 , Colleen M Niswender  2 , Corey R Hopkins  4
Affiliations

Discovery and characterization of a novel series of N-phenylsulfonyl-1H-pyrrole picolinamides as positive allosteric modulators of the metabotropic glutamate receptor 4 (mGlu4)

Rocco D Gogliotti et al. Bioorg Med Chem Lett. .

Abstract

Herein we report the synthesis and characterization of a novel series of N-phenylsulfonyl-1H-pyrrole picolinamides as novel positive allosteric modulators of mGlu4. We detail our work towards finding phenyl replacements for the core scaffold of previously reported phenyl sulfonamides and phenyl sulfone compounds. Our efforts culminated in the identification of N-(1-((3,4-dimethylphenyl)sulfonyl)-1H-pyrrol-3-yl)picolinamide as a potent PAM of mGlu4.

Keywords: Metabotropic glutamate receptor 4; PK; Phenyl replacement; Positive allosteric modulator (PAM); Pyrrole sulfonamide.

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Figures

Figure 1
Figure 1
Previously disclosed phenylsulfonamide and phenylsulfone mGlu4 PAMs.
Scheme 1
Scheme 1
Reagents and conditions. (a) Picolinyl chloride·HCl, diisopropylethylamine, CH2Cl2, 24–39%; (b) Pd2(dba)3, XantPhos, HSCH2Ar, diisopropylethylamine, 1,4-dioxane, 100 °C, 51–87%; (c) m-CPBA, CH2Cl2, 38–87%.
Scheme 2
Scheme 2
Reagents and conditions. (a) DBU, ArSO2Cl or BnSO2Cl, CH2Cl2, 50–96%; (b) EtOH, Ra–Ni, 40 psi H2, 2 h; 93–97%; (c) diisopropylethylamine, picolinyl chloride, CH2Cl2, 39–43%.
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