5m7m | pdb_00005m7m
Novel Imidazo[1,2-a]pyridine Derivatives with Potent Autotaxin/ENPP2 Inhibitor Activity
Structural highlights
Function[ENPP2_HUMAN] Hydrolyzes lysophospholipids to produce lysophosphatidic acid (LPA) in extracellular fluids. Major substrate is lysophosphatidylcholine. Also can act on sphingosylphosphphorylcholine producing sphingosine-1-phosphate, a modulator of cell motility. Can hydrolyze, in vitro, bis-pNPP, to some extent pNP-TMP, and barely ATP. Involved in several motility-related processes such as angiogenesis and neurite outgrowth. Acts as an angiogenic factor by stimulating migration of smooth muscle cells and microtubule formation. Stimulates migration of melanoma cells, probably via a pertussis toxin-sensitive G protein. May have a role in induction of parturition. Possible involvement in cell proliferation and adipose tissue development. Tumor cell motility-stimulating factor.[1] [2] [3] Publication Abstract from PubMedAutotaxin (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. 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 J Med Chem. 2017 Aug 18. doi: 10.1021/acs.jmedchem.7b00647. PMID:28731719[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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