title: A novel inhaled Syk inhibitor blocks mast cell degranulation and early asthmatic response.
abstract: Spleen tyrosine kinase (Syk) is essential for signal transduction of immunoreceptors. Inhibition of Syk abrogates mast cell degranulation and B cell responses. We hypothesized that Syk inhibition in the lung by inhaled route could block airway mast cells degranulation and the early asthmatic response without the need of systemic exposure. We discovered LAS189386, a novel Syk inhibitor with suitable properties for inhaled administration. The aim of this study was to characterize the in vitro and in vivo profile of LAS189386. The compound was profiled in Syk enzymatic assay, against a panel of selected kinases and in Syk-dependent cellular assays in mast cells and B cells. Pharmacokinetics and in vivo efficacy was assessed by intratracheal route. Airway resistance and mast cell degranulation after OVA challenge was evaluated in an ovalbumin-sensitized Brown Norway rat model. LAS189386 potently inhibits Syk enzymatic activity (IC50 7.2 nM), Syk phosphorylation (IC50 41 nM), LAD2 cells degranulation (IC50 56 nM), and B cell activation (IC50 22 nM). LAS189386 inhibits early asthmatic response and airway mast cell degranulation without affecting systemic mast cells. The present results support the hypothesis that topical inhibition of Syk in the lung, without systemic exposure, is sufficient to inhibit EAR in rats. Syk inhibition by inhaled route constitutes a promising therapeutic option for asthma.
authors.affiliation: Almirall R&D Center, Sant Feliu de Llobregat, Barcelona, Spain. Electronic address: isabel.ramis@almirall.com.
authors.forename: Isabel
authors.initials: I
authors.lastname: Ramis
authors.affiliation: Almirall R&D Center, Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Otal
authors.affiliation: Almirall R&D Center, Sant Feliu de Llobregat, Barcelona, Spain. Electronic address: cristina.carreno@almirall.com.
authors.forename: Cristina
authors.initials: C
authors.lastname: Carreño
authors.affiliation: Almirall R&D Center, Sant Feliu de Llobregat, Barcelona, Spain. Electronic address: anna.domenech@almirall.com.
authors.forename: Anna
authors.initials: A
authors.lastname: Domènech
authors.affiliation: Almirall R&D Center, Sant Feliu de Llobregat, Barcelona, Spain. Electronic address: peter.eichhorn@almirall.com.
authors.forename: Peter
authors.initials: P
authors.lastname: Eichhorn
authors.affiliation: Almirall R&D Center, Sant Feliu de Llobregat, Barcelona, Spain. Electronic address: adelina_orellana@hotmail.com.
authors.forename: Adelina
authors.initials: A
authors.lastname: Orellana
authors.affiliation: Almirall R&D Center, Sant Feliu de Llobregat, Barcelona, Spain. Electronic address: monica.maldonado@almirall.com.
authors.forename: Mónica
authors.initials: M
authors.lastname: Maldonado
authors.affiliation: Almirall R&D Center, Sant Feliu de Llobregat, Barcelona, Spain. Electronic address: jorgedealba@hotmail.com.
authors.forename: Jorge
authors.initials: J
authors.lastname: De Alba
authors.affiliation: Almirall R&D Center, Sant Feliu de Llobregat, Barcelona, Spain. Electronic address: neusprats@movistar.com.
authors.forename: Neus
authors.initials: N
authors.lastname: Prats
authors.affiliation: Almirall-Barcelona Science Park Unit, Barcelona Science Park, Barcelona, Spain. Electronic address: jcfernandez@pcb.ub.es.
authors.forename: Joan-Carles
authors.initials: JC
authors.lastname: Fernández
authors.affiliation: Almirall R&D Center, Sant Feliu de Llobregat, Barcelona, Spain. Electronic address: bernat.vidal@almirall.com.
authors.forename: Bernat
authors.initials: B
authors.lastname: Vidal
authors.affiliation: Almirall R&D Center, Sant Feliu de Llobregat, Barcelona, Spain. Electronic address: montse.miralpeix@almirall.com.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Miralpeix
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001249:Asthma / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D053961:Azabicyclo Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001402:B-Lymphocytes / Q000187:drug effects / Q000502:physiology; D015550:Cell Degranulation / Q000187:drug effects; D002460:Cell Line; D004195:Disease Models, Animal; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D011914:Rats, Inbred BN; D017208:Rats, Wistar; D000072377:Syk Kinase
chemical_list: C000608387:1-(2-(2,5-diazabicyclo(2.2.1)hept-2-yl)pyridin-4-yl)-N-pyrazin-2-yl-1H-indazol-3-amine; D053961:Azabicyclo Compounds; D007191:Indazoles; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606898:Syk protein, rat
keywords: Asthma; Brown Norway rat; Early asthmatic response; Inhalation; Mast cells; Syk