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Article 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC12142581 | PMC |
| http://dx.doi.org/10.1021/acschemneuro.5c00277 | DOI Listing |
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