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Benzoxaboroles-Novel Autotaxin Inhibitors

Benzoxaboroles-Novel Autotaxin Inhibitors

Kristina Kraljić, Dubravko Jelić, Dinko Žiher, Adam Cvrtila, Snježana Dragojević, Verona Sinković, Milan Mesić

Molecules. 2019 Sep 20;24(19):3419.

PMID: 31547058

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 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).

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1312201005	HA155		1312201-00-5	Price

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