5 years ago

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

Discovery, Structure–Activity Relationship, and Binding Mode of an Imidazo[1,2-a]pyridine Series of Autotaxin Inhibitors
Veronique Roncoroni, Mia Jans, Katja Conrath, Bertrand Heckmann, Thierry Christophe, Denis Annoot, Luce Lepissier, Agnès Joncour, Reginald Brys, Nele Vandervoort, Willem Jan Hengeveld, Jörg Heiermann, Sandrine Le Tallec, Virginie Labeguere, Damien Fleury, Gregor Pilzak, Laëtitia Cherel, Christopher Housseman, René Galien, Natacha Bienvenu, Christelle David, Patrick Mollat, Xavier Bock, Sameh Soror, Alain Monjardet, Nicolas Triballeau, Emanuelle Wakselman, Ellen van der Aar, Nicolas Desroy, Jan Steyaert, Lionel Vercheval, Alexandre Wohlkonig, Robert Touitou, Christophe Peixoto
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.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00647

DOI: 10.1021/acs.jmedchem.7b00647

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