作者
Nicolas Desroy,Christopher Gaëtan Housseman,Xavier Marie Bock,Agnès Marie Joncour,Natacha Bienvenu,Laëtitia Cherel,Virginie Labeguere,Emilie Rondet,Christophe Peixoto,Jean-Marie Grassot,Picolet Olivier Laurent,Denis Annoot,Nicolas Triballeau,Alain Monjardet,Emanuelle Wakselman,Veronique Roncoroni,Sandrine Le Tallec,Roland Blanque,C. Cottereaux,Nele Vandervoort,Thierry Christophe,Patrick Mollat,Marieke Lamers,M. Auberval,Boska Hrvacic,Jovica Ralić,Line Oste,Ellen van der Aar,Reginald Brys,Bertrand Heckmann
摘要
Autotaxin is a circulating enzyme with a major role in the production of lysophosphatic acid (LPA) species in blood. A role for the autotaxin/LPA axis has been suggested in many disease areas including pulmonary fibrosis. Structural modifications of the known autotaxin inhibitor lead compound 1, to attenuate hERG inhibition, remove CYP3A4 time-dependent inhibition, and improve pharmacokinetic properties, led to the identification of clinical candidate GLPG1690 (11). Compound 11 was able to cause a sustained reduction of LPA levels in plasma in vivo and was shown to be efficacious in a bleomycin-induced pulmonary fibrosis model in mice and in reducing extracellular matrix deposition in the lung while also reducing LPA 18:2 content in bronchoalveolar lavage fluid. Compound 11 is currently being evaluated in an exploratory phase 2a study in idiopathic pulmonary fibrosis patients.