2. Academic Validation
  3. Discovery and Early Clinical Development of Isobutyl 1-[8-Methoxy-5-(1-oxo-3 H-isobenzofuran-5-yl)-[1,2,4]triazolo[1,5- a]pyridin-2-yl]cyclopropanecarboxylate (LEO 39652), a Novel "Dual-Soft" PDE4 Inhibitor for Topical Treatment of Atopic Dermatitis

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

  • J Med Chem. 2020 Dec 10;63(23):14502-14521. doi: 10.1021/acs.jmedchem.0c00797.
Jens Larsen,  Maja Lambert,  Henrik Pettersson,  Thomas Vifian,  Mogens Larsen,  Anna Ollerstam,  Pontus Hegardt,  Cecilia Eskilsson,  Steen Laursen,  Anders Soehoel,  Tine Skak-Nielsen,  Lene M Hansen,  Nina Ø Knudsen,  Stefan Eirefelt,  Morten D Sørensen,  Tatiana G Stilou,  Simon F Nielsen
PMID: 33054196 DOI: 10.1021/acs.jmedchem.0c00797
Abstract

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.

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