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Discovery of VU6016235: A Highly Selective, Orally Bioavailable, and Structurally Distinct Tricyclic M Muscarinic Acetylcholine Receptor Positive Allosteric Modulator (PAM)

Authors

Engers JL Julie L , Baker LA Logan A , Chang S Sichen , Luscombe VB Vincent B , Rodriguez AL Alice L , Niswender CM Colleen M , Cho HP Hyekyung P , Bubser M Michael , Gray AT Analisa Thompson , Jones CK Carrie K , Peng W Weimin , Rook JM Jerri M , Bridges TM Thomas M , Boutaud O Olivier , Conn PJ P Jeffrey , Engers DW Darren W , Lindsley CW Craig W , Temple KJ Kayla J .
ACS chemical neuroscience. 2024 09 24; 15(20).
3744-54

Abstract

Herein, we report structure-activity relationship (SAR) studies to develop novel tricyclic M PAM scaffolds with improved pharmacological properties. This endeavor involved a “tie-back” strategy to replace a 5-amino-2,4-dimethylthieno[2,3-]pyrimidine-6-carboxamide core, which led to the discovery of two novel tricyclic cores. While both tricyclic cores displayed low nanomolar potency against both human and rat M and were highly brain-penetrant, the 2,4-dimethylpyrido[4′,3′:4,5]thieno[2,3-]pyrimidine tricycle core provided lead compound, , with an overall superior pharmacological and drug metabolism and pharmacokinetics (DMPK) profile, as well as efficacy in a preclinical antipsychotic animal model.