title: Discovery of 7-azaindole derivatives as potent Orai inhibitors showing efficacy in a preclinical model of asthma.
abstract: Synthesis and SAR of a series of 7-azaindoles as Orai channel inhibitors showing good potency inhibiting IL-2 production in Jurkat cells is described. Compound 14d displaying best pharmacokinetic properties was further characterized in a model of allergen induced asthma showing inhibition in the number of eosinophils in BALF. High lipophilicity remains as one of the main challenges for this class of compounds.
authors.affiliation: Almirall Research Center, Almirall, Ctra. Laureà Miró 408, E-08980 St. Feliu de Llobregat, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Esteve
authors.affiliation: Almirall Research Center, Almirall, Ctra. Laureà Miró 408, E-08980 St. Feliu de Llobregat, Barcelona, Spain.
authors.forename: Jacob
authors.initials: J
authors.lastname: González
authors.affiliation: Almirall Research Center, Almirall, Ctra. Laureà Miró 408, E-08980 St. Feliu de Llobregat, Barcelona, Spain.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Gual
authors.affiliation: Almirall Research Center, Almirall, Ctra. Laureà Miró 408, E-08980 St. Feliu de Llobregat, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Vidal
authors.affiliation: Almirall Research Center, Almirall, Ctra. Laureà Miró 408, E-08980 St. Feliu de Llobregat, Barcelona, Spain.
authors.forename: Soledad
authors.initials: S
authors.lastname: Alzina
authors.affiliation: Almirall Research Center, Almirall, Ctra. Laureà Miró 408, E-08980 St. Feliu de Llobregat, Barcelona, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Sentellas
authors.affiliation: Almirall Research Center, Almirall, Ctra. Laureà Miró 408, E-08980 St. Feliu de Llobregat, Barcelona, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Jover
authors.affiliation: Almirall Research Center, Almirall, Ctra. Laureà Miró 408, E-08980 St. Feliu de Llobregat, Barcelona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Horrillo
authors.affiliation: Almirall Research Center, Almirall, Ctra. Laureà Miró 408, E-08980 St. Feliu de Llobregat, Barcelona, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: De Alba
authors.affiliation: Almirall Research Center, Almirall, Ctra. Laureà Miró 408, E-08980 St. Feliu de Llobregat, Barcelona, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Miralpeix
authors.affiliation: Almirall Research Center, Almirall, Ctra. Laureà Miró 408, E-08980 St. Feliu de Llobregat, Barcelona, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Tarrasón
authors.affiliation: Almirall Research Center, Almirall, Ctra. Laureà Miró 408, E-08980 St. Feliu de Llobregat, Barcelona, Spain. Electronic address: bernat.vidal@almirall.com.
authors.forename: Bernat
authors.initials: B
authors.lastname: Vidal
mesh_terms: D000818:Animals; D001249:Asthma; D001372:Aza Compounds / Q000737:chemistry; D002121:Calcium Channel Blockers / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015220:Calcium Channels / Q000737:chemistry* / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy / Q000276:immunology; D007211:Indoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D007376:Interleukin-2 / Q000097:blood / Q000378:metabolism; D019169:Jurkat Cells; D008861:Microsomes / Q000378:metabolism; D008954:Models, Biological; D010047:Ovalbumin / Q000276:immunology; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011758:Pyrroles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D001372:Aza Compounds; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D007211:Indoles; D007376:Interleukin-2; D011725:Pyridines; D011758:Pyrroles; D010047:Ovalbumin
keywords: CRAC channel; IL-2 inhibitors; LAD2; OVA model; Orai inhibitors