Discovery of new quinoline ether inhibitors with high affinity and selectivity for PDGFR tyrosine kinases

Patrick A Plé; Frédéric Jung; Sue Ashton; Laurent Hennequin; Romuald Laine; Christine Lambert-van der Brempt; Rémy Morgentin; Georges Pasquet; Sian Taylor

doi:10.1016/j.bmcl.2012.03.074

Discovery of new quinoline ether inhibitors with high affinity and selectivity for PDGFR tyrosine kinases

Bioorg Med Chem Lett. 2012 May 1;22(9):3050-5. doi: 10.1016/j.bmcl.2012.03.074. Epub 2012 Mar 28.

Authors

Patrick A Plé¹, Frédéric Jung, Sue Ashton, Laurent Hennequin, Romuald Laine, Christine Lambert-van der Brempt, Rémy Morgentin, Georges Pasquet, Sian Taylor

Affiliation

¹ AstraZeneca, Centre de Recherches, BP 1050, 51689 Reims Cedex 2, France. patrick.ple@astrazeneca.com

PMID: 22497760
DOI: 10.1016/j.bmcl.2012.03.074

Abstract

A new series of quinoline ether inhibitors, which potently and selectively inhibit PDGFR tyrosine kinases, is described in this Letter. Compounds 23 and 33 are selective, low nanomolar inhibitors of PDGFRα and β, display good pharmacokinetics in rat and dog and are active in vivo at low doses when given orally twice daily. Further evaluation of these compounds is warranted.

MeSH terms

Animals
Dogs
Dose-Response Relationship, Drug
Drug Discovery
Ethers / pharmacology*
Protein-Tyrosine Kinases / antagonists & inhibitors
Quinolines / pharmacology*
Rats
Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors*

Substances

Ethers
Quinolines
Protein-Tyrosine Kinases
Receptors, Platelet-Derived Growth Factor