6ZBA

Crystal structure of PDE4D2 in complex with inhibitor LEO39652

This is a non-PDB format compatible entry.

Summary for 6ZBA

• Entry DOI: 10.2210/pdb6zba/pdb
• Descriptor: cAMP-specific 3',5'-cyclic phosphodiesterase 4D, 2-methylpropyl 1-[8-methoxy-5-(1-oxidanylidene-3~{H}-2-benzofuran-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropane-1-carboxylate, 1,2-ETHANEDIOL, ... (7 entities in total)
• Functional Keywords: phosphodiesterase, phosphodiesterase inhibitor, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 169570.11

Authors

Akutsu, M.,Hakansson, M.,Welin, M.,Svensson, A.,Logan, D.T.,Sorensen, M.D. (deposition date: 2020-06-08, release date: 2020-09-23, Last modification date: 2024-01-24)

Primary citation

Larsen, J.,Lambert, M.,Pettersson, H.,Vifian, T.,Larsen, M.,Ollerstam, A.,Hegardt, P.,Eskilsson, C.,Laursen, S.,Soehoel, A.,Skak-Nielsen, T.,Hansen, L.M.,Knudsen, N.O.,Eirefelt, S.,Sorensen, M.D.,Stilou, T.G.,Nielsen, S.F.
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., 63:14502-14521, 2020

PubMed 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 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.

PubMed: 33054196
DOI: 10.1021/acs.jmedchem.0c00797

Experimental method

X-RAY DIFFRACTION (1.6 Å)