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. 2017 May 11;60(9):3580-3590.
doi: 10.1021/acs.jmedchem.7b00032. Epub 2017 May 1.

Discovery of 2-[[2-Ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2-a]pyridin-3-yl]methylamino]-4-(4-fluorophenyl)thiazole-5-carbonitrile (GLPG1690), a First-in-Class Autotaxin Inhibitor Undergoing Clinical Evaluation for the Treatment of Idiopathic Pulmonary Fibrosis

Nicolas Desroy  1 , Christopher Housseman  1 , Xavier Bock  1 , Agnès Joncour  1 , Natacha Bienvenu  1 , Laëtitia Cherel  1 , Virginie Labeguere  1 , Emilie Rondet  1 , Christophe Peixoto  1 , Jean-Marie Grassot  1 , Olivier Picolet  1 , Denis Annoot  1 , Nicolas Triballeau  1 , Alain Monjardet  1 , Emanuelle Wakselman  1 , Veronique Roncoroni  1 , Sandrine Le Tallec  1 , Roland Blanque  1 , Celine Cottereaux  1 , Nele Vandervoort  2 , Thierry Christophe  2 , Patrick Mollat  1 , Marieke Lamers  3 , Marielle Auberval  1 , Boska Hrvacic  4 , Jovica Ralic  4 , Line Oste  2 , Ellen van der Aar  2 , Reginald Brys  2 , Bertrand Heckmann  1
Affiliations

Discovery of 2-[[2-Ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2-a]pyridin-3-yl]methylamino]-4-(4-fluorophenyl)thiazole-5-carbonitrile (GLPG1690), a First-in-Class Autotaxin Inhibitor Undergoing Clinical Evaluation for the Treatment of Idiopathic Pulmonary Fibrosis

Nicolas Desroy et al. J Med Chem. .

Abstract

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.

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