Design, synthesis, and biological evaluation of 2,4-dihydropyrano[2,3-c]pyrazole derivatives as autotaxin inhibitors.

Autor: Pantsar T; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland. Electronic address: tatu.pantsar@uef.fi., Singha P; School of Medicine, Institute of Biomedicine, Faculty of Health Sciences, University of Eastern 5 Finland, 70211 Kuopio, Finland., Nevalainen TJ; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland., Koshevoy I; Department of Chemistry, University of Eastern Finland, P.O. Box 111, FIN-80101 Joensuu, Finland., Leppänen J; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland., Poso A; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland; Department of Internal Medicine VIII, University Hospital Tuebingen, 72076 Tuebingen, Germany., Niskanen JMA; School of Medicine, Institute of Biomedicine, Faculty of Health Sciences, University of Eastern 5 Finland, 70211 Kuopio, Finland., Pasonen-Seppänen S; School of Medicine, Institute of Biomedicine, Faculty of Health Sciences, University of Eastern 5 Finland, 70211 Kuopio, Finland., Savinainen JR; School of Medicine, Institute of Biomedicine, Faculty of Health Sciences, University of Eastern 5 Finland, 70211 Kuopio, Finland., Laitinen T; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland., Laitinen JT; School of Medicine, Institute of Biomedicine, Faculty of Health Sciences, University of Eastern 5 Finland, 70211 Kuopio, Finland.
Jazyk: angličtina
Zdroj: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences [Eur J Pharm Sci] 2017 Sep 30; Vol. 107, pp. 97-111. Date of Electronic Publication: 2017 Jul 05.
DOI: 10.1016/j.ejps.2017.07.002
Abstrakt: Inhibition of Autotaxin (ATX) is a potential treatment strategy for several diseases, including tumors with elevated ATX-lysophosphatidic acid (LPA) signaling. Combining structure-based virtual screening together with hen egg-white Autotaxin (ewATX) activity assays enabled the discovery of novel small-molecule ATX inhibitors with a 2,4-dihydropyrano[2,3-c]pyrazole scaffold. These compounds are suggested to bind to the lipophilic pocket, leaving the active site unrestrained. Our most potent compound, (S)-6-amino-4-(3,4-dichlorophenyl)-3-(4-[(4-fluorobenzyl)oxy]phenyl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile [(S)-25], inhibited human ATX (hATX) with an IC 50 -value of 134nM. It also blocked ATX-evoked but not LPA-mediated A2058 melanoma cell migration. Noteworthy, molecular modeling correctly predicted the biologically active enantiomer of 2,4-dihydropyrano[2,3-c]pyrazoles, as verified by compound crystallization and activity assays. Our study established the ewATX activity assay as a valid and affordable tool in ATX inhibitor discovery. Overall, our study offers novel insights and approaches into design of novel ATX inhibitors targeting the hydrophobic pocket instead of the active site.
(Copyright © 2017 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE