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. 2017 Sep 14;60(17):7371-7392.
doi: 10.1021/acs.jmedchem.7b00647. Epub 2017 Aug 18.

Discovery, Structure-Activity Relationship, and Binding Mode of an Imidazo[1,2-a]pyridine Series of Autotaxin Inhibitors

Agnès Joncour  1 , Nicolas Desroy  1 , Christopher Housseman  1 , Xavier Bock  1 , Natacha Bienvenu  1 , Laëtitia Cherel  1 , Virginie Labeguere  1 , Christophe Peixoto  1 , Denis Annoot  1 , Luce Lepissier  1 , Jörg Heiermann  2 , Willem Jan Hengeveld  2 , Gregor Pilzak  2 , Alain Monjardet  1 , Emanuelle Wakselman  1 , Veronique Roncoroni  1 , Sandrine Le Tallec  1 , René Galien  1 , Christelle David  1 , Nele Vandervoort  3 , Thierry Christophe  3 , Katja Conrath  3 , Mia Jans  3 , Alexandre Wohlkonig  4 , Sameh Soror  4 , Jan Steyaert  4 , Robert Touitou  1 , Damien Fleury  1 , Lionel Vercheval  1 , Patrick Mollat  1 , Nicolas Triballeau  1 , Ellen van der Aar  3 , Reginald Brys  3 , Bertrand Heckmann  1
Affiliations

Discovery, Structure-Activity Relationship, and Binding Mode of an Imidazo[1,2-a]pyridine Series of Autotaxin Inhibitors

Agnès Joncour et al. J Med Chem. .

Erratum in

  • Correction to Discovery, Structure-Activity Relationship, and Binding Mode of an Imidazo[1,2- a]pyridine Series of Autotaxin Inhibitors.
    Joncour A, Desroy N, Housseman C, Bock X, Bienvenu N, Cherel L, Labeguere V, Peixoto C, Annoot D, Lepissier L, Heiermann J, Hengeveld WJ, Pilzak G, Monjardet A, Wakselman E, Roncoroni V, Le Tallec S, Galien R, David C, Vandervoort N, Christophe T, Conrath K, Jans M, Wohlkonig A, Soror S, Steyaert J, Touitou R, Fleury D, Vercheval L, Mollat P, Triballeau N, van der Aar E, Brys R, Heckmann B. Joncour A, et al. J Med Chem. 2018 May 10;61(9):4270. doi: 10.1021/acs.jmedchem.8b00579. Epub 2018 Apr 19. J Med Chem. 2018. PMID: 29672037 No abstract available.

Abstract

Autotaxin (ATX) is a secreted enzyme playing a major role in the production of lysophosphatidic acid (LPA) in blood through hydrolysis of lysophosphatidyl choline (LPC). The ATX-LPA signaling axis arouses a high interest in the drug discovery industry as it has been implicated in several diseases including cancer, fibrotic diseases, and inflammation, among others. An imidazo[1,2-a]pyridine series of ATX inhibitors was identified out of a high-throughput screening (HTS). A cocrystal structure with one of these compounds and ATX revealed a novel binding mode with occupancy of the hydrophobic pocket and channel of ATX but no interaction with zinc ions of the catalytic site. Exploration of the structure-activity relationship led to compounds displaying high activity in biochemical and plasma assays, exemplified by compound 40. Compound 40 was also able to decrease the plasma LPA levels upon oral administration to rats.

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