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Keywords = lysophosphaditic acid

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22 pages, 3467 KiB  
Article
Benzoxaboroles—Novel Autotaxin Inhibitors
by Kristina Kraljić, Dubravko Jelić, Dinko Žiher, Adam Cvrtila, Snježana Dragojević, Verona Sinković and Milan Mesić
Molecules 2019, 24(19), 3419; https://doi.org/10.3390/molecules24193419 - 20 Sep 2019
Cited by 20 | Viewed by 5671
Abstract
Autotaxin (ATX) is an extracellular enzyme that hydrolyses lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), which has a role in the mediation of inflammation, fibrosis and cancer. ATX is a drug target that has been the focus of many research groups during the last [...] Read more.
Autotaxin (ATX) is an extracellular enzyme that hydrolyses lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), which has a role in the mediation of inflammation, fibrosis and cancer. ATX is a drug target that has been the focus of many research groups during the last ten years. To date, only one molecule, Ziritaxestat (GLPG1690) has entered the clinic; it is currently in Phase 3 clinical trials for idiopathic pulmonary fibrosis. Other small molecules, with different binding modes, have been investigated as ATX inhibitors for cancer including compounds possessing a boronic acid motif such as HA155. In this work, we targeted new, improved inhibitors of ATX that mimic the important interactions of boronic acid using a benzoxaborole motif as the acidic warhead. Furthermore, we aimed to improve the plasma stability of the new compounds by using a more stable core spacer than that embedded in HA155. Compounds were synthesized, evaluated for their ATX inhibitory activity and ADME properties in vitro, culminating in a new benzoxaborole compound, 37, which retains the ATX inhibition activity of HA155 but has improved ADME properties (plasma protein binding, good kinetic solubility and rat/human plasma stability). Full article
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