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Discovery of 7-azaindole derivatives as potent Orai inhibitors showing efficacy in a preclinical model of asthma.

Esteve, Cristina; González, Jacob; Gual, Sílvia; Vidal, Laura; Alzina, Soledad; Sentellas, Sonia; Jover, Irene; Horrillo, Raquel; De Alba, Jorge; Miralpeix, Montserrat; Tarrasón, Gema; Vidal, Bernat.

Bioorg Med Chem Lett ; 25(6): 1217-22, 2015 Mar 15.

Article in English | MEDLINE | ID: mdl-25690784

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.

Subject(s)

Calcium Channel Blockers/chemistry , Calcium Channels/chemistry , Indoles/chemistry , Pyridines/chemistry , Pyrroles/chemistry , Animals , Asthma , Aza Compounds/chemistry , Calcium Channel Blockers/pharmacokinetics , Calcium Channel Blockers/therapeutic use , Calcium Channels/metabolism , Disease Models, Animal , Drug Evaluation, Preclinical , Half-Life , Humans , Hypersensitivity/drug therapy , Hypersensitivity/immunology , Indoles/pharmacokinetics , Indoles/therapeutic use , Interleukin-2/blood , Interleukin-2/metabolism , Jurkat Cells , Microsomes/metabolism , Models, Biological , Ovalbumin/immunology , Protein Binding , Pyridines/pharmacokinetics , Pyridines/therapeutic use , Pyrroles/pharmacokinetics , Pyrroles/therapeutic use , Rats , Structure-Activity Relationship

ABSTRACT

Subject(s)

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