Potent, Selective Pyrrolopyrimidine PDE11A4 Inhibitors with Improved Pharmaceutical Properties

  • ACS Med Chem Lett. 2026 Jan 30;17(2):547-553. doi: 10.1021/acsmedchemlett.5c00756.
Shams Ul Mahmood  1 ,  Rama Krishna Boddu  1 ,  Jeremy Eberhard  2 ,  Charles S Hoffman  2 ,  John Gordon  3 ,  Dennis Colussi  3 ,  Wayne Childers  3 ,  Elvis Amurrio  4 ,  Marie Danaher  4 ,  Michy P Kelly  4 ,  David P Rotella  1
Affiliations
  • 1. Department of Chemistry and Biochemistry, Sokol Institute of Pharmaceutical Life Sciences, Montclair State University, Montclair, New Jersey 07043, United States.
  • 2. Biology Department, Boston College, Chestnut Hill, Massachusetts 02467, United States.
  • 3. Moulder Center for Drug Discovery, Temple University, Philadelphia, Pennsylvania 19140, United States.
  • 4. Department of Neurobiology, University of Maryland School of Medicine, Center for Research on Aging, University of Maryland School of Medicine, Baltimore, Maryland 21201, United States.
PMID: 41704346 DOI: 10.1021/acsmedchemlett.5c00756
Abstract

Previous work demonstrated target engagement with an orally bioavailable, potent, selective PDE11A4 inhibitor in the mouse hypothalamus. This compound was limited by low aqueous solubility, stimulating the need for alternative leads with improved pharmaceutical properties to carry out efficacy studies. This paper outlines optimization of a pyrrolopyrimidine hit leading to a potent, selective PDE11A4 inhibitor with improved pharmaceutical properties and promising activity in cell-based models of enzyme activity.

Keywords
LLPS activity; PDE11A4; cell-based activity; pharmaceutical properties; phosphodiesterase inhibitor.
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