March 3, 2026ACS Medicinal Chemistry Letters0 citationsOpen Access

Potent, Selective Pyrrolopyrimidine PDE11A4 Inhibitors with Improved Pharmaceutical Properties

SMShams ul Mahmood RBRama Krishna Boddu JEJeremy Eberhard

Key Points

Improved pharmaceutical properties enhance bioavailability, enabling more effective PDE11A4 inhibition.
The newly optimized inhibitor demonstrates potent activity, particularly in cell-based models of enzyme activity.
Observational analysis of compound effectiveness indicates a significant advancement over previous formulations.
Potential limitations include initial solubility constraints, necessitating further refinement for future applications.

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.

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