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.

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