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Article Abstract
The lack of potent and selective tool compounds with pharmaceutically favorable properties limits the in vivo understanding of muscarinic acetylcholine receptor subtype 5 (M) biology. Previously, we presented a highly potent and selective M antagonist VU6019650 with a suboptimal clearance profile as our second-generation tool compound. Herein, we disclose our ongoing efforts to generate next-generation M antagonists with improved clearance profiles. A mix and match approach between VU6019650 (lead) and VU0500325 (HTS hit) generated a piperidine amide-based novel M antagonist series. Several analogs within this series, including 29f, provided good on-target potency with improved clearance profiles, though room for improvement remains.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10939060 | PMC |
| http://dx.doi.org/10.1016/j.bmcl.2022.128988 | DOI Listing |
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