1. Academic Validation
  2. 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

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

  • J Med Chem. 2017 May 11;60(9):3580-3590. doi: 10.1021/acs.jmedchem.7b00032.
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

Affiliations

  • 1 Galapagos SASU , 102 Avenue Gaston Roussel, 93230 Romainville, France.
  • 2 Galapagos NV , Generaal De Wittelaan L11 A3, 2800 Mechelen, Belgium.
  • 3 Charles River Laboratories , Chesterford Research Park, CB10 1XL Saffron Walden, United Kingdom.
  • 4 Fidelta Ltd. , Prilaz baruna Filipovića 29, Zagreb, HR-10000, Croatia.
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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