title: Discovery of a novel isoxazoline derivative of prednisolone endowed with a robust anti-inflammatory profile and suitable for topical pulmonary administration.
abstract: A novel glucocorticoids series of (GCs), 6α,9α-di-Fluoro 3-substituted C-16,17-isoxazolines was designed, synthesised and their structure-activity relationship was evaluated with glucocorticoid receptor (GR) binding studies together with GR nuclear translocation cell-based assays. This strategy, coupled with in silico modelling analysis, allowed for the identification of Cpd #15, an isoxazoline showing a sub-nanomolar inhibitory potency (IC50=0.84 nM) against TNFα-evoked IL-8 release in primary human airways smooth muscle cells. In Raw264.7 mouse macrophages, Cpd #15 inhibited LPS-induced NO release with a potency (IC50=6 nM)>10-fold higher with respect to Dexamethasone. Upon intratracheal (i.t.) administration, Cpd #15, at 0.1 μmol/kg significantly inhibited and at 1 μmol/kg fully counteracted eosinophilic infiltration in a model of allergen-induced pulmonary inflammation in rats. Moreover, Cpd #15 proved to be suitable for pulmonary topical administration given its sustained lung retention (t1/2=6.5h) and high pulmonary levels (>100-fold higher than plasma levels) upon intratracheal administration in rats. In summary, Cpd #15 displays a pharmacokinetic and pharmacodynamic profile suitable for topical treatment of conditions associated with pulmonary inflammation such as asthma and COPD.
authors.affiliation: Chemistry Research and Drug Design Department, Chiesi Farmaceutici S.p.A., Parma, Italy. Electronic address: e.ghidini@chiesi.com.
authors.forename: E
authors.initials: E
authors.lastname: Ghidini
authors.affiliation: Chemistry Research and Drug Design Department, Chiesi Farmaceutici S.p.A., Parma, Italy.
authors.forename: A M
authors.initials: AM
authors.lastname: Capelli
authors.affiliation: Pharmacology and Toxicology Department, Chiesi Farmaceutici S.p.A., Parma, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Carnini
authors.affiliation: Pharmacokinetic Department, Chiesi Farmaceutici S.p.A., Parma, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Cenacchi
authors.affiliation: Pharmacology and Toxicology Department, Chiesi Farmaceutici S.p.A., Parma, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Marchini
authors.affiliation: Nikem Research Srl, Baranzate di Bollate (Mi), Italy.
authors.forename: A
authors.initials: A
authors.lastname: Virdis
authors.affiliation: Chiman Srl, via Reggio Calabria, 12 Rottofreno (PC), Italy.
authors.forename: A
authors.initials: A
authors.lastname: Italia
authors.affiliation: Pharmacology and Toxicology Department, Chiesi Farmaceutici S.p.A., Parma, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Facchinetti
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004802:Eosinophilia / Q000276:immunology; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D007555:Isoxazoles / Q000737:chemistry*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology; D011239:Prednisolone / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D016209:Interleukin-8; D007555:Isoxazoles; D008070:Lipopolysaccharides; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; C404226:TSC22D3 protein, human; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D010047:Ovalbumin; D011239:Prednisolone
keywords: Corticosteroid; GILZ; Isoxazoline; Nuclear translocation; Ovalbumin; PK profile