Targeting the hinge glycine flip and the activation loop: novel approach to potent p38α inhibitors.

The p38 MAP kinase is a key player in signaling pathways regulating the biosynthesis of inflammatory cytokines. Small molecule p38 inhibitors suppress the production of these cytokines. Therefore p38 is a promising drug target for novel anti-inflammatory drugs. In this study, we report novel dibenzepinones, dibenzoxepines, and benzosuberones as p38α MAP kinase inhibitors. Previously reported dibenzepinones and dibenzoxepines were chemically modified by introduction of functional groups or removal of a phenyl ring. This should result in targeting of the hydrophobic region I, the "deep pocket", and the hinge glycine flip of the kinase. Potent inhibitors with IC(50) values in the single digit nanomolar range (up to 3 nM) were identified. Instead of targeting the "deep pocket" in the DFG-out conformation, interactions with the DFG-motif in the in-conformation could be observed by protein X-ray crystallography.

Design, synthesis and SAR of phenylamino-substituted 5,11-dihydro-dibenzo[a,d]cyclohepten-10-ones and 11H-dibenzo[b,f]oxepin-10-ones as p38 MAP kinase inhibitors.

The p38 MAP kinase is a key enzyme in inflammatory diseases as it is involved in the biosynthesis of proinflammatory cytokines such as TNF-alpha and IL-1beta. Small molecule p38 inhibitors suppress the production of these cytokines and therefore p38 is a promising drug target for novel anti-inflammatory therapeutics. In this study, we report the design, synthesis, and SAR of novel N-substituted 11H-dibenzo[b,f]oxepin-10-ones and 5,11-dihydro-dibenzo[a,d]cyclohepten-10-ones as p38 inhibitors.

N-[3-(5-Oxo-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-2-ylamino)phen-yl]furan-3-carboxamide.

In the title compound, C(26)H(20)N(2)O(3), the two aromatic rings of the tricyclic unit are oriented at a dihedral angle of 54.53 (9)°. The crystal structure displays inter-molecular N-H⋯O hydrogen bonding.

1-[4-(2-Amino-anilino)phen-yl]-2,2,2-trifluoro-ethanone.

In the title compound, C(14)H(11)F(3)N(2)O, the two aromatic rings are oriented at a dihedral angle of 70.84 (8)°. The crystal structure displays inter-molecular N-H⋯O and N-H⋯F inter-actions.

N-{2-Methyl-5-[(5-oxo-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-2-yl)amino]-phen-yl}benzamide.

In the title compound, C(29)H(24)N(2)O(2), the two aromatic rings of the tricyclic unit are oriented at a dihedral angle of 32.27 (8)°. In the crystal N-H⋯O hydrogen bonds link the mol-ecules into chains along the a axis. Further N-H⋯·O inter-actions link the chains.