Design and Synthesis of Highly Selective Brain Penetrant p38α Mitogen-Activated Protein Kinase Inhibitors.

Stress-induced p38α mitogen-activated protein (MAP) kinase activation modulates cytokine overproduction and is associated with neuroinflammation and neurodegeneration. As a potential therapeutic approach, novel Skepinone-based p38α MAP kinase inhibitors were optimized to cross the blood-brain barrier via either amino acid transporters or hydrophobic diffusion. To enhance absorption from the oral route, we used methyl ester prodrugs of the active carboxy analogs. Of these, 3-(8-((2,4-difluorophenyl)amino)-5-oxo-10,11-dihydro--dibenzo[,][7]annulene-3-carboxamido)propanoic acid (; p38α, IC = 5.5 nM) and 4-(8-((2,4-difluorophenyl)amino)-5-oxo-10,11-dihydro-5-dibenzo[,][7]annulene-3-carboxamido)butanoic acid (; p38α, IC = 12 nM) had brain-to-plasma ratios of 1.4 and 4.4, respectively. Compound , 3-(8-((2-aminophenyl)amino)-5-oxo-10,11-dihydro-5-dibenzo[,][7]annulene-3-carboxamido)propanoic acid (p38α, IC = 1.0 nM), the Skepinone-N counterpart of , was most present in the mouse brain (brain-to-plasma ratio of 4.7; 0.4 mg/kg p.o., 2 h, 580 nmol/kg). Compounds , , and were p38α-MAP-kinase-selective, metabolically stable, hERG nonbinding, and able to modulate IL-6 and TNF-α production in cell-based assays.