Benzoxaboroles-Novel Autotaxin Inhibitors.
Molecules
; 24(19)2019 Sep 20.
Article
in En
| MEDLINE
| ID: mdl-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).
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Lysophospholipids
/
Lysophosphatidylcholines
Limits:
Animals
/
Humans
Language:
En
Journal:
Molecules
Journal subject:
BIOLOGIA
Year:
2019
Document type:
Article
Affiliation country:
Croacia