McGowan Kevin M, Nance Kellie D, Cho Hykeyung P, Bridges Thomas M, Conn P Jeffrey, Jones Carrie K, Lindsley Craig W
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
Bioorg Med Chem Lett. 2017 Mar 15;27(6):1356-1359. doi: 10.1016/j.bmcl.2017.02.020. Epub 2017 Feb 13.
This letter describes the continued optimization of M NAM ML375 (VU0483253). While a valuable in vivo tool compound, ML375has an excessively long elimination half-life in rat (t=80h), which can be problematic in certain rodent addiction paradigms (e.g., reinstatement). Thus, we required an M NAM of comparable potency to ML375, but with a rat t of less than 4h. 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 M NAM, with high CNS penetration, excellent selectivity versus M and the desired short half-life (t=2.3h) in rat.
这封信描述了M NAM ML375（VU0483253）的持续优化。虽然ML375是一种有价值的体内工具化合物，但它在大鼠体内的消除半衰期过长（t = 80小时），这在某些啮齿动物成瘾模型（如复吸）中可能会出现问题。因此，我们需要一种与ML375效力相当，但大鼠半衰期小于4小时的M NAM。该化学类型存在陡峭的构效关系，在此我们详细介绍了苯胺替代物，它们比ML375有一些改进，但未能取得进展。最终，在9b-苯环上引入一个甲基起到了代谢分流的作用，得到了（S）-11（VU6008667），一种效力相当的M NAM，具有高脑渗透性，对M有优异的选择性，且在大鼠体内具有所需的短半衰期（t = 2.3小时）。
