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Discovery, Structure–Activity Relationship, and Binding Mode of an Imidazo[1,2-a]pyridine Series of Autotaxin Inhibitors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-08-18 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00647 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
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-08-18 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00647 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
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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.
中文翻译：
咪唑并[1,2- a ]吡啶系列自分泌抑制因子抑制剂的发现，结构-活性关系和结合方式
Autotaxin（ATX）是一种分泌的酶，在血液中通过溶血磷脂酰胆碱（LPC）的水解在溶血磷脂酸（LPA）的生产中起主要作用。ATX-LPA信号转导引起了药物开发行业的高度关注，因为它已涉及多种疾病，包括癌症，纤维化疾病和炎症等。咪唑[1,2- a从高通量筛选（HTS）中鉴定出ATX抑制剂的]吡啶系列。这些化合物之一与ATX的共晶结构揭示了一种新型的结合模式，占据了ATX的疏水口袋和通道，但与催化位点的锌离子没有相互作用。对结构-活性关系的探索导致化合物在生化和血浆分析中显示出高活性，例如化合物40。口服给予大鼠后，化合物40还能够降低血浆LPA水平。
更新日期：2017-08-19
中文翻译：
咪唑并[1,2- a ]吡啶系列自分泌抑制因子抑制剂的发现，结构-活性关系和结合方式
Autotaxin（ATX）是一种分泌的酶，在血液中通过溶血磷脂酰胆碱（LPC）的水解在溶血磷脂酸（LPA）的生产中起主要作用。ATX-LPA信号转导引起了药物开发行业的高度关注，因为它已涉及多种疾病，包括癌症，纤维化疾病和炎症等。咪唑[1,2- a从高通量筛选（HTS）中鉴定出ATX抑制剂的]吡啶系列。这些化合物之一与ATX的共晶结构揭示了一种新型的结合模式，占据了ATX的疏水口袋和通道，但与催化位点的锌离子没有相互作用。对结构-活性关系的探索导致化合物在生化和血浆分析中显示出高活性，例如化合物40。口服给予大鼠后，化合物40还能够降低血浆LPA水平。
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