1445656-87-0Relevant articles and documents
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
Larsen, Jens,Lambert, Maja,Pettersson, Henrik,Vifian, Thomas,Larsen, Mogens,Ollerstam, Anna,Hegardt, Pontus,Eskilsson, Cecilia,Laursen, Steen,Soehoel, Anders,Skak-Nielsen, Tine,Hansen, Lene M.,Knudsen, Nina ?.,Eirefelt, Stefan,S?rensen, Morten D.,Stilou, Tatiana G.,Nielsen, Simon F.
, p. 14502 - 14521 (2020/11/19)
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.
