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

• Published in: Journal of medicinal chemistry 2022-01, Vol.65 (2), p.1225-1242
• Main Authors: Tormählen, Niklas M, Martorelli, Mariella, Kuhn, Annette, Maier, Florian, Guezguez, Jamil, Burnet, Michael, Albrecht, Wolfgang, Laufer, Stefan A, Koch, Pierre
• Format: Article
• Language: English
• Subjects: Animals; Brain - drug effects; Brain - metabolism; Drug Design; Female; Interleukin-6 - metabolism; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Molecular Docking Simulation; Molecular Structure; Oncogene Proteins - metabolism; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - pharmacology; Pyrimidines - chemistry; Transcriptional Regulator ERG - metabolism; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c01773

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-5H-dibenzo­[a,d]­[7]­annulene-3-carboxamido)­propanoic acid (43; p38α, IC50 = 5.5 nM) and 4-(8-((2,4-difluorophenyl)­amino)-5-oxo-10,11-dihydro-5H-dibenzo­[a,d]­[7]­annulene-3-carboxamido)­butanoic acid (44; p38α, IC50 = 12 nM) had brain-to-plasma ratios of 1.4 and 4.4, respectively. Compound 70, 3-(8-((2-aminophenyl)­amino)-5-oxo-10,11-dihydro-5H-dibenzo­[a,d]­[7]­annulene-3-carboxamido)­propanoic acid (p38α, IC50 = 1.0 nM), the Skepinone-N counterpart of 43, 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 43, 44, and 70 were p38α-MAP-kinase-selective, metabolically stable, hERG nonbinding, and able to modulate IL-6 and TNF-α production in cell-based assays.