Biphenyl amide p38 kinase inhibitors 3: Improvement of cellular and in vivo activity

The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules

“…p38α MAP kinase, a serine/threonine kinase, has been implicated in the production of inflammatory cytokines such as TNFα and IL-1β, thus making this kinase an attractive target for developing effective anti-rheumatic drugs. 94 Angell et al, 95 Leu74 and Phe169. These findings also revealed the strict steric requirements of this pocket in the enzyme.…”

A Randomized, Placebo-controlled Trial of the Analgesic Efficacy and Safety of the p38 MAP Kinase Inhibitor, Losmapimod, in Patients With Neuropathic Pain From Lumbosacral Radiculopathy

“…[17][18][19] Recent years have seen the discovery and exploratory development of several p38 MAPK inhibitors that may find utility in pain management. [20][21][22][23] Intrathecal administration of p38 MAPK inhibitors has consistently been shown to be efficacious in preclinical models of neuropathic pain. 9,11,24,25 Few studies, however, have been undertaken to establish the relevance of p38 MAPK inhibition in humans.…”

A Comprehensive Structural Overview of p38α Mitogen‐Activated Protein Kinase in Complex with ATP‐Site and Non‐ATP‐Site Binders

“…[33] The only chemical difference between these two is the group involved in the interaction with the LR. The more potent derivative 19 interacts with key residues Glu71 and Asp168, whereas contact with Glu71 is absent for compound 18 ( Figure 6).…”