Discovery of Pre-Clinical Candidate VU6008055/AF98943: A Highly Selective, Orally Bioavailable, and Structurally Distinct Tricyclic M(4) Muscarinic Acetylcholine Receptor Positive Allosteric Modulator (PAM) with Robust In Vivo Efficacy.

Herein, we report the structure-activity relationship to develop novel tricyclic M(4) positive allosteric modulator scaffolds with improved pharmacological properties. This endeavor involved modifying a 5-amino-3,4-dimethylthieno[2,3-c]pyridazine-6-carboxamide core via a "tie-back" strategy to discover a novel tricyclic 3,4-dimethylpyrimido[4',5':4,5]thieno[2,3-c]pyridazine core. From this exercise, VU6008055/AF98943 was identified as a preclinical candidate, which displays low nanomolar potency against both human and rat M(4). Moreover, VU6008055 is highly brain penetrant, has an overall superior pharmacological and DMPK profile to previously reported M(4) PAMs, and demonstrates efficacy in preclinical models of antipsychotic-like activity.