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. 2025 Apr 22;16(5):865-874.
doi: 10.1021/acsmedchemlett.5c00119. eCollection 2025 May 8.

Discovery of Thieno[3,2- b]pyridine-5-carboxamide and 2,3-Difluorobenzamide Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5

Katherine E Crocker  1   2 , Scott H Henderson  1   2 , Rory A Capstick  1   2 , David L Whomble  1   2 , Aaron M Bender  1   2 , Andrew S Felts  1   2 , Changho Han  1   2 , Julie L Engers  1   2 , Natasha B Billard  1   2 , Mallory A Maurer  1   2 , Hyekyung P Cho  1   2 , Alice L Rodriguez  1   2 , Colleen M Niswender  1   2   3   4   5 , Jordan O'Neill  1   2 , Katherine J Watson  1   2 , Sichen Chang  1   2 , Anna L Blobaum  1   2 , Olivier Boutaud  1   2 , Weimin Peng  2 , Jerri M Rook  2 , P Jeffrey Conn  1   2   5 , Craig W Lindsley  1   2   6   3 , Kayla J Temple  1   2
Affiliations

Discovery of Thieno[3,2- b]pyridine-5-carboxamide and 2,3-Difluorobenzamide Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5

Katherine E Crocker et al. ACS Med Chem Lett. .

Abstract

This Letter describes the discovery of novel mGlu5 NAMs VU6031545 and VU6024945. Starting from previously reported picolinamide compounds, a structure-activity relationship study of various core isosteres was conducted, leading to the identification of thieno[3,2-b]pyridine-5-carboxamide and 2,3-difluorobenzamide as competent core replacements. These compounds are highly potent as well as brain penetrant with an IVIVC agreement and improved oral bioavailability in rats.

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Conflict of interest statement

The authors declare the following competing financial interest(s): The authors hold IP on mGlu5 NAMs.

Figures

Figure 1
Figure 1
Selective mGlu5 NAMs based on an aryl/heterobiaryl acetylene pharmacophore (highlighted in blue).
Figure 2
Figure 2
Nonacetylene, selective mGlu5 NAMs.
Figure 3
Figure 3
Previously published scaffold-hopping exercises that led to the discovery of mGlu5 NAMs 11 and 13. Further medicinal chemistry efforts led to novel and potent mGlu5 NAMs 14 and 15.
Scheme 1
Scheme 1. Synthesis of mGlu5 NAM Analogues 19a–19g and 22
Reagents and conditions: (i) KHMDS, DMF, 0 °C 1–18 h, 44%–92%; (ii) KHMDS, DMF, 0–60 °C, 48 h, 63%–91% (for 19d); (iii) K2CO3, DMF, microwave irradiation at 150 °C, 20 min, 61% (for 19g); (iv) 2M NaOH(aq) or 2M LiOH(aq), 1,4-dioxane or THF, 60–100 °C, 2–8 h, 51%–100%; (v) 2M NaOH(aq), 1,4-dioxane, microwave irradiation at 120 °C, 30 min, 99%; (vi) POCl3, R1NH2, pyridine, 23 °C, 30 min, 15%–95%; (vii) NaOH(aq), 1,4-dioxane, 100 °C, 18 h, 99%; (viii) POCl3, pyridine, 23 °C, 30 min, 74%; (ix) R2OH, KOtBu, DMSO, 65 °C, 19%–97%.
Scheme 2
Scheme 2. Synthesis of mGlu5 NAM Analogues 27a–27g
Reagents and conditions: (i) (R)-tetrahydrofuran-3-ol, NaH, NMP, 0–23 °C, 1 h, 36%; (ii) Pd(dppf)Cl2•DCM, NaOAc, EtOH/DMF, CO(g), 70 °C, 3 h, 90%; (iii) 2M NaOH(aq) or 2M LiOH(aq), THF, 1–2 h, 85%–99%; (iv) 2M LiOH(aq), THF, 60 °C, 8 h, 85% (for 30f); (v) POCl3, R1NH2, pyridine, 23 °C, 30 min, 2%–47%; (vi) (S)-tetrahydrofuran-3-ol, DIAD, PPh3, THF, 23 °C, 1 h, 62%–74%; (vii) (R)-tetrahydrofuran-3-ol, KHMDS, THF, microwave irradiated at 150 °C, 15 min, 99%; (viii) (R)-tetrahydrofuran-3-ol, KOtBu, DMF, 80 °C, 30 min, 99% (for 30e); (ix) (R)-tetrahydrofuran-3-ol, KHMDS, DMF, 0 °C, 30 min, 58%–72% (for 30f–30g).
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