Identification and SAR of a new series of thieno[3,2-d]pyrimidines as Tpl2 kinase inhibitors

Yike Ni; Ariamala Gopalsamy; Derek Cole; Yonghan Hu; Rajiah Denny; Manus Ipek; Julie Liu; Julie Lee; J Perry Hall; Michael Luong; Jean-Baptiste Telliez; Lih-Ling Lin

doi:10.1016/j.bmcl.2011.07.069

Identification and SAR of a new series of thieno[3,2-d]pyrimidines as Tpl2 kinase inhibitors

Bioorg Med Chem Lett. 2011 Oct 1;21(19):5952-6. doi: 10.1016/j.bmcl.2011.07.069. Epub 2011 Jul 26.

Authors

Yike Ni¹, Ariamala Gopalsamy, Derek Cole, Yonghan Hu, Rajiah Denny, Manus Ipek, Julie Liu, Julie Lee, J Perry Hall, Michael Luong, Jean-Baptiste Telliez, Lih-Ling Lin

Affiliation

¹ Medicinal Chemistry, Pfizer, 200 Cambridge Park Drive, Cambridge, MA 02140, USA. [email protected]

PMID: 21862328
DOI: 10.1016/j.bmcl.2011.07.069

Abstract

We report here the synthesis and SAR of a new series of thieno[3,2-d]pyrimidines as potent Tpl2 kinase inhibitors. The proposed binding mode suggests the potential flipped binding mode depending on the substitution. Biacore studies show evidence of binding of these molecules to the protein kinase. The kinome inhibition profile of these molecules suggests good selectivity.

MeSH terms

Animals
Drug Discovery
Drug Evaluation, Preclinical
Humans
Inhibitory Concentration 50
MAP Kinase Kinase Kinases / antagonists & inhibitors*
MAP Kinase Kinase Kinases / metabolism
Microsomes, Liver
Molecular Targeted Therapy
Monocytes
Neoplasms / drug therapy
Phosphorylation
Protein Binding
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins / antagonists & inhibitors*
Proto-Oncogene Proteins / metabolism
Pyrimidines / chemistry
Rats
Structure-Activity Relationship
Substrate Specificity

Substances

Protein Kinase Inhibitors
Proto-Oncogene Proteins
Pyrimidines
MAP Kinase Kinase Kinases
MAP3K8 protein, human