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
  • 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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