Discovery and Early Clinical Development of Isobutyl 1‑[8-Methoxy-5-(1-oxo‑3<i>H</i>‑isobenzofuran-5-yl)-[1,2,4]triazolo[1,5‑<i>a</i>]­pyridin-2-yl]­cyclopropane­carboxylate (LEO 39652), a Novel “Dual-Soft” PDE4 Inhibitor for Topical Treatment of Atopic Dermatitis

We describe the design of a novel PDE4 scaffold and the exploration of the dual-soft concept to reduce systemic side effects via rapid elimination: introducing ester functionalities that can be inactivated in blood as well as by the liver (dual-soft) while being stable in human skin. Compound 40 was selected as a clinical candidate as it was potent and rapidly degraded by blood and liver to inactive metabolites and because in preclinical studies it showed high exposure at the target organ: the skin. Preclinical and clinical data are presented confirming the value of the dual-soft concept in reducing systemic exposure.