Department of Chemistry and Biochemistry, Montclair State University, 1 Normal Avenue, Montclair, New Jersey 07043, United States.
Sokol Institute for Pharmaceutical Life Sciences, Montclair State University, Montclair, New Jersey 07043, United States.
J Med Chem. 2024 Oct 10;67(19):17774-17784. doi: 10.1021/acs.jmedchem.4c01794. Epub 2024 Sep 25.
PDE11A4 is a target of interest for the treatment of age-related memory disorders. A previous report from our laboratories described an amide series of potent, selective PDE11A4 inhibitors that was metabolically unstable. Investigation of heterocyclic amide isosteres for the labile amide moiety revealed distinct structure-activity relationships and identified several compounds with potency comparable to the amide series. This manuscript describes the characterization of structure-activity and structure-property relationships in this set, leading to the identification of an orally bioavailable, brain-penetrant, selective and potent PDE11A4 inhibitor. Target engagement experiments demonstrated PDE11A4 inhibition in the hypothalamus of mice that was absent in PDE11A4 knock out animals.
PDE11A4 是治疗与年龄相关的记忆障碍的一个有前景的靶点。我们实验室的先前报告描述了一系列具有很强的选择性 PDE11A4 抑制剂的酰胺，但其代谢不稳定。对不稳定酰胺部分的杂环酰胺同系物的研究揭示了不同的构效关系，并确定了一些具有与酰胺系列相当效力的化合物。本文描述了该系列化合物的构效和构性关系的表征，从而确定了一种具有口服生物利用度、脑渗透性、选择性和高效的 PDE11A4 抑制剂。靶标结合实验表明，在所研究的化合物中，PDE11A4 在小鼠的下丘脑被抑制，而在 PDE11A4 敲除动物中则没有被抑制。
