2. Academic Validation
  3. 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

  • J Med Chem. 2017 Sep 14;60(17):7371-7392. 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
Affiliations

Affiliations

  • 1 Galapagos SASU , 102 Avenue Gaston Roussel, 93230 Romainville, France.
  • 2 Mercachem , Kerkenbos 1013, 6546 Nijmegen, The Netherlands.
  • 3 Galapagos NV , Generaal De Wittelaan L11 A3, 2800 Mechelen, Belgium.
  • 4 VIB Structural Biology Research Center, Vrije Universiteit Brussel , 1050 Brussel, Belgium.
PMID: 28731719 DOI: 10.1021/acs.jmedchem.7b00647
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.

Figures
Products