Atopic dermatitis (AD) is a chronic inflammatory skin condition significantly impacting the quality of life in both pediatric and adult patient populations. Inhibition of phosphodiesterase 4 (PDE4) is an established mechanism leading to therapeutic benefits for patients with inflammatory disorders. Topical PDE4 inhibitors have been shown to be clinically advantageous for the treatment of AD and additional compounds are currently in development. Building upon our understanding of the inflammatory conditions, we embarked on the discovery of the next generation of topical boron-based PDE4 inhibitors. Utilizing a “topical by intent” approach, we focused on high target potency, high systemic clearance, and suitable solubility and permeability parameters acceptable for topical formulation. This led to the discovery of PF-07038124 as a novel chiral oxaborole-based PDE inhibitor. The novelty and synthetic complexity of these chiral oxaboroles required invention of new synthetic approaches since there were no reported asymmetric routes to the oxaborole ring system contained within PF-07938124. Herein we will describe the identification, optimization, and synthetic preparation of PF-07038124, which was selected for clinical development for the topical treatment of inflammatory conditions including AD.

The Discovery of PF-07038124, a boron-containing Phosphodiesterase 4 inhibitor for the treatment of Inflammatory Diseases.

ACS Spring 2022

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