Discovery of LAS101057: A Potent, Selective, and Orally Efficacious A2B Adenosine Receptor Antagonist

  • ACS Med Chem Lett. 2010 Dec 20;2(3):213-8. doi: 10.1021/ml100249e.
Paul Eastwood  1 ,  Cristina Esteve  1 ,  Jacob González  1 ,  Silvia Fonquerna  1 ,  Josep Aiguadé  1 ,  Inés Carranco  1 ,  Teresa Doménech  1 ,  Mònica Aparici  1 ,  Montserrat Miralpeix  1 ,  Joan Albertí  1 ,  Mónica Córdoba  1 ,  Raquel Fernández  1 ,  Mercè Pont  1 ,  Núria Godessart  1 ,  Neus Prats  1 ,  María Isabel Loza  2 ,  María Isabel Cadavid  2 ,  Arsenio Nueda  1 ,  Bernat Vidal  1
Affiliations
  • 1. Almirall, R&D Centre, Ctra. Laureà Miró 408, 08980-Sant Feliu de Llobregat, Barcelona, Spain.
  • 2. Discovery group "BioFarma", Faculty of Pharmacy, University of Santiago de Compostela, 15782-Santiago de Compostela, Spain.
PMID: 24900298 DOI: 10.1021/ml100249e
Abstract

The structure-activity relationships for a series of pyrazine-based A2B Adenosine Receptor antagonists are described. From this work, LAS101057 (17), a potent, selective, and orally efficacious A2B receptor antagonist, was identified as a clinical development candidate. LAS101057 inhibits agonist-induced IL-6 production in human fibroblasts and is active in an ovalbumin (OVA)-sensitized mouse model after oral administration, reducing airway hyperresponsiveness to methacholine, Th2 cytokine production, and OVA-specific IgE levels.

Keywords
A2B adenosine receptor antagonist; clinical candidate; ovalbumin mouse model.