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Discovery of 4-(5-Membered)Heteroarylether-6-methylpicolinamide Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5

Authors

Childress ES Elizabeth S , Capstick RA Rory A , Crocker KE Katherine E , Ledyard ML Miranda L , Bender AM Aaron M , Maurer MA Mallory A , Billard NB Natasha B , Cho HP Hyekyung P , Rodriguez AL Alice L , Niswender CM Colleen M , Peng W Weimin , Rook JM Jerri M , Chang S Sichen , Blobaum AL Anna L , Boutaud O Olivier , Thompson Gray A Analisa , Jones CK Carrie K , Conn PJ P Jeffrey , Felts AS Andrew S , Lindsley CW Craig W , Temple KJ Kayla J .
ACS medicinal chemistry letters. 2024 11 18; 15(12).
2210-2219

Abstract

This Letter details our efforts to develop novel, non-acetylene-containing metabotropic glutamate receptor subtype 5 (mGlu) negative allosteric modulators (NAMs) with improved pharmacological properties. This endeavor involved replacing the ether-linked pyrimidine moiety, a metabolic liability, with various 5-membered heterocycles. From this exercise, we identified , a highly brain penetrant and selective mGlu NAM which displayed moderate potency against both human and rat mGlu. Moreover, has overall improved pharmacological and drug metabolism and pharmacokinetic profiles when compared to its predecessor compounds. Most notably, exhibits low predicted human hepatic clearance, a clean cytochrome P450 profile, and minimal inhibition of the dopamine transporter.