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

[Display omitted] 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 inh...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2015-03, Vol.25 (6), p.1217-1222
Hauptverfasser:	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
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Asthma Aza Compounds - chemistry Calcium Channel Blockers - chemistry Calcium Channel Blockers - pharmacokinetics Calcium Channel Blockers - therapeutic use Calcium Channels - chemistry Calcium Channels - metabolism CRAC channel Disease Models, Animal Drug Evaluation, Preclinical Half-Life Humans Hypersensitivity - drug therapy Hypersensitivity - immunology IL-2 inhibitors Indoles - chemistry Indoles - pharmacokinetics Indoles - therapeutic use Interleukin-2 - blood Interleukin-2 - metabolism Jurkat Cells LAD2 Microsomes - metabolism Models, Biological Orai inhibitors OVA model Ovalbumin - immunology Protein Binding Pyridines - chemistry Pyridines - pharmacokinetics Pyridines - therapeutic use Pyrroles - chemistry Pyrroles - pharmacokinetics Pyrroles - therapeutic use Rats Structure-Activity Relationship
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Zusammenfassung:	[Display omitted] 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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2015.01.063