2. Academic Validation
  3. First Demonstration of In Vivo PDE11A4 Target Engagement for Potential Treatment of Age-Related Memory Disorders

First Demonstration of In Vivo PDE11A4 Target Engagement for Potential Treatment of Age-Related Memory Disorders

  • J Med Chem. 2024 Oct 10;67(19):17774-17784. doi: 10.1021/acs.jmedchem.4c01794.
Shams Ul Mahmood 1 2,  Jeremy Eberhard 3,  Charles S Hoffman 3,  Dennis Colussi 4,  John Gordon 4,  Wayne Childers 4,  Elvis Amurrio 5,  Janvi Patel 5,  Michy P Kelly 5 6,  David P Rotella 1 2
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, Montclair State University, 1 Normal Avenue, Montclair, New Jersey 07043, United States.
  • 2 Sokol Institute for Pharmaceutical Life Sciences, Montclair State University, Montclair, New Jersey 07043, United States.
  • 3 Biology Department, Boston College, Chestnut Hill, Massachusetts 02467, United States.
  • 4 Moulder Center for Drug Discovery Research, Temple University, Philadelphia, Pennsylvania 19140, United States.
  • 5 Department of Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, United States.
  • 6 Center for Research on Aging, University of Maryland, Baltimore School of Medicine, Baltimore, Maryland 21201, United States.
PMID: 39321314 DOI: 10.1021/acs.jmedchem.4c01794
Abstract

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.

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