Synthesis and SAR of new pyrazolo[4,3-h]quinazoline-3-carboxamide derivatives as potent and selective MPS1 kinase inhibitors

Marina Caldarelli; Mauro Angiolini; Teresa Disingrini; Daniele Donati; Marco Guanci; Stefano Nuvoloni; Helena Posteri; Francesca Quartieri; Marco Silvagni; Riccardo Colombo

doi:10.1016/j.bmcl.2011.05.122

Synthesis and SAR of new pyrazolo[4,3-h]quinazoline-3-carboxamide derivatives as potent and selective MPS1 kinase inhibitors

Bioorg Med Chem Lett. 2011 Aug 1;21(15):4507-11. doi: 10.1016/j.bmcl.2011.05.122. Epub 2011 Jun 14.

Authors

Marina Caldarelli¹, Mauro Angiolini, Teresa Disingrini, Daniele Donati, Marco Guanci, Stefano Nuvoloni, Helena Posteri, Francesca Quartieri, Marco Silvagni, Riccardo Colombo

Affiliation

¹ Nerviano Medical Sciences srl, Business Unit Oncology, Nerviano, MI, Italy. marina.caldarelli@nervianoms.com

PMID: 21723120
DOI: 10.1016/j.bmcl.2011.05.122

Abstract

The synthesis and SAR of a series of novel pyrazolo-quinazolines as potent and selective MPS1 inhibitors are reported. We describe the optimization of the initial hit, identified by screening the internal library collection, into an orally available, potent and selective MPS1 inhibitor.

MeSH terms

Administration, Oral
Amides / chemical synthesis
Amides / chemistry*
Amides / pharmacokinetics
Animals
Cell Cycle Proteins / antagonists & inhibitors*
Cell Cycle Proteins / metabolism
Mice
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacokinetics
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / metabolism
Protein-Tyrosine Kinases
Quinazolines / chemistry*
Structure-Activity Relationship

Substances

Amides
Cell Cycle Proteins
Protein Kinase Inhibitors
Quinazolines
Protein-Tyrosine Kinases
Protein Serine-Threonine Kinases
TTK protein, human