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

  • Bioorg Med Chem Lett. 2015 Mar 15;25(6):1217-22. doi: 10.1016/j.bmcl.2015.01.063.
Cristina Esteve  1 ,  Jacob González  1 ,  Sílvia Gual  1 ,  Laura Vidal  1 ,  Soledad Alzina  1 ,  Sonia Sentellas  1 ,  Irene Jover  1 ,  Raquel Horrillo  1 ,  Jorge De Alba  1 ,  Montserrat Miralpeix  1 ,  Gema Tarrasón  1 ,  Bernat Vidal  2
Affiliations
  • 1. Almirall Research Center, Almirall, Ctra. Laureà Miró 408, E-08980 St. Feliu de Llobregat, Barcelona, Spain.
  • 2. Almirall Research Center, Almirall, Ctra. Laureà Miró 408, E-08980 St. Feliu de Llobregat, Barcelona, Spain. Electronic address: [email protected].
PMID: 25690784 DOI: 10.1016/j.bmcl.2015.01.063
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.

Keywords
CRAC channel; IL-2 inhibitors; LAD2; OVA model; Orai inhibitors.