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Discovery of Pre-Clinical Candidate /: A Highly Selective, Orally Bioavailable, and Structurally Distinct Tricyclic M Muscarinic Acetylcholine Receptor Positive Allosteric Modulator (PAM) with Robust In Vivo Efficacy

Authors

Engers JL Julie L , Bollinger SR Sean R , Gregro AR Alison R , Capstick RA Rory A , Spearing PK Paul K , Long MF Madeline F , Tarr JC James C , Watson KJ Katherine J , Chang S Sichen , Luscombe VB Vincent B , Rodriguez AL Alice L , Cho HP Hyekyung P , Qi A Aidong , Niswender CM Colleen M , Bubser M Michael , Gould RW Robert W , Robb WH William Hudson , Byun N Nellie , Gore J John , Jones CK Carrie K , Thomsen MS Morten S , 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. 2025 05 26; 16(11).
2141-2162

Abstract

Herein, we report the structure-activity relationship to develop novel tricyclic M positive allosteric modulator scaffolds with improved pharmacological properties. This endeavor involved modifying a 5-amino-3,4-dimethylthieno[2,3-]pyridazine-6-carboxamide core via a “tie-back” strategy to discover a novel tricyclic 3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-]pyridazine core. From this exercise, / was identified as a preclinical candidate, which displays low nanomolar potency against both human and rat M. Moreover, is highly brain penetrant, has an overall superior pharmacological and DMPK profile to previously reported M PAMs, and demonstrates efficacy in preclinical models of antipsychotic-like activity.