Amide-based inhibitors of p38alpha MAP kinase. Part 2: design, synthesis and SAR of potent N-pyrimidyl amides

Richland Tester; Xuefei Tan; Gregory R Luedtke; Imad Nashashibi; Kurt Schinzel; Weiling Liang; Joon Jung; Sundeep Dugar; Albert Liclican; Jocelyn Tabora; Daniel E Levy; Steven Do

doi:10.1016/j.bmcl.2010.02.090

Amide-based inhibitors of p38alpha MAP kinase. Part 2: design, synthesis and SAR of potent N-pyrimidyl amides

Bioorg Med Chem Lett. 2010 Apr 15;20(8):2560-3. doi: 10.1016/j.bmcl.2010.02.090. Epub 2010 Mar 2.

Authors

Richland Tester¹, Xuefei Tan, Gregory R Luedtke, Imad Nashashibi, Kurt Schinzel, Weiling Liang, Joon Jung, Sundeep Dugar, Albert Liclican, Jocelyn Tabora, Daniel E Levy, Steven Do

Affiliation

¹ Department of Medicinal Chemistry, Scios Inc. Fremont, CA 94555, USA.

PMID: 20346659
DOI: 10.1016/j.bmcl.2010.02.090

Abstract

Optimization of a tri-substituted N-pyridyl amide led to the discovery of a new class of potent N-pyrimidyl amide based p38alpha MAP kinase inhibitors. Initial SAR studies led to the identification of 5-dihydrofuran as an optimal hydrophobic group. Additional side chain modifications resulted in the introduction of hydrogen bond interactions. Through extensive SAR studies, analogs bearing free amino groups and alternatives to the parent (S)-alpha-methyl benzyl moiety were identified. These compounds exhibited improved cellular activities and maintained balance between p38alpha and CYP3A4 inhibition.

MeSH terms

Amides / chemistry
Amides / pharmacology*
Drug Design
Models, Molecular
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / chemistry*
Structure-Activity Relationship

Substances

Amides
Protein Kinase Inhibitors
Pyrimidines