2. Academic Validation
  3. 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.
PMID: 28414242 DOI: 10.1021/acs.jmedchem.7b00032
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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