title: Novel Roflumilast analogs as soft PDE4 inhibitors.
abstract: PDE4 inhibitors are of high interest for treatment of a wide range of inflammatory or autoimmune diseases. Their potential however has not yet been realized due to target-associated side effects, resulting in a low therapeutic window. We herein report the design, synthesis and evaluation of novel PDE4 inhibitors containing a γ-lactone structure. Such molecules are designed to undergo metabolic inactivation when entering circulation, thereby limiting systemic exposure and reducing the risk for side effects. The resulting inhibitors were highly active on both PDE4B1 and PDE4D2 and underwent rapid degradation in human plasma by paraoxonase 1. In contrast, their metabolites displayed markedly reduced permeability and/or on-target activity.
authors.affiliation: Amakem N.V. Agoralaan A bis, 3590 Diepenbeek, Belgium. Electronic address: sandro.boland@amakem.com.
authors.forename: Sandro
authors.initials: S
authors.lastname: Boland
authors.affiliation: Amakem N.V. Agoralaan A bis, 3590 Diepenbeek, Belgium.
authors.forename: Jo
authors.initials: J
authors.lastname: Alen
authors.affiliation: Amakem N.V. Agoralaan A bis, 3590 Diepenbeek, Belgium.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Bourin
authors.affiliation: Amakem N.V. Agoralaan A bis, 3590 Diepenbeek, Belgium.
authors.forename: Karolien
authors.initials: K
authors.lastname: Castermans
authors.affiliation: Amakem N.V. Agoralaan A bis, 3590 Diepenbeek, Belgium.
authors.forename: Nicki
authors.initials: N
authors.lastname: Boumans
authors.affiliation: Amakem N.V. Agoralaan A bis, 3590 Diepenbeek, Belgium.
authors.forename: Laura
authors.initials: L
authors.lastname: Panitti
authors.affiliation: Amakem N.V. Agoralaan A bis, 3590 Diepenbeek, Belgium.
authors.forename: Jessica
authors.initials: J
authors.lastname: Vanormelingen
authors.affiliation: Amakem N.V. Agoralaan A bis, 3590 Diepenbeek, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Leysen
authors.affiliation: Amakem N.V. Agoralaan A bis, 3590 Diepenbeek, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Defert
mesh_terms: D000631:Aminopyridines / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D003521:Cyclopropanes / Q000097:blood / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006868:Hydrolysis; D015394:Molecular Structure; D058988:Phosphodiesterase 4 Inhibitors / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; D058988:Phosphodiesterase 4 Inhibitors; C424423:Roflumilast; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517360:PDE4B protein, human; C517376:PDE4D protein, human
keywords: COPD; Esterase; PDE4 inhibitors; SAR; Soft drug