Continued optimization of the M5 NAM ML375: Discovery of VU6008667, an M5 NAM with high CNS penetration and a desired short half-life in rat for addiction studies |
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| Authors: | Kevin M. McGowan Kellie D. Nance Hykeyung P. Cho Thomas M. Bridges P. Jeffrey Conn Carrie K. Jones Craig W. Lindsley |
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| Affiliation: | 1. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA;2. Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA;3. Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA;4. Vanderbilt Institute of Chemical Biology and Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, TN 37232, USA |
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| Abstract: | This letter describes the continued optimization of M5 NAM ML375 (VU0483253). While a valuable in vivo tool compound, ML375 has an excessively long elimination half-life in rat (t1/2 = 80 h), which can be problematic in certain rodent addiction paradigms (e.g., reinstatement). Thus, we required an M5 NAM of comparable potency to ML375, but with a rat t1/2 of less than 4 h. Steep SAR plagued this chemotype, and here we detail aniline replacements that offered some improvements over ML375, but failed to advance. Ultimately, incorporation of a single methyl group to the 9b-phenyl ring acted as a metabolic shunt, providing (S)-11 (VU6008667), an equipotent M5 NAM, with high CNS penetration, excellent selectivity versus M1–4 and the desired short half-life (t1/2 = 2.3 h) in rat. |
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| Keywords: | Muscarinic acetylcholine receptor Pharmacokinetics CNS penetration Structure-Activity Relationship (SAR) |
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