Shams ul Mahmood, Jeremy Eberhard, Charles S. Hoffman, Dennis Colussi, John Gordon, Wayne Childers, Elvis Amurrio, Janvi Patel, Michy P. Kelly, David P. Rotella
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First Demonstration of In Vivo PDE11A4 Target Engagement for Potential Treatment of Age-Related Memory Disorders
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.
期刊介绍:
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.