sd-0006 and Inflammation

SD0006 is a diarylpyrazole that was prepared as an inhibitor of p38 kinase-alpha (p38alpha). In vitro, SD0006 was selective for p38alpha kinase over 50 other kinases screened (including p38gamma and p38delta with modest selectivity over p38beta). Crystal structures with p38alpha show binding at the ATP site with additional residue interactions outside the ATP pocket unique to p38alpha that can confer advantages over other ATP competitive inhibitors. Direct correlation between inhibition of p38alpha activity and that of lipopolysaccharide-stimulated TNFalpha release was established in cellular models and in vivo, including a phase 1 clinical trial. Potency (IC(50)) for inhibiting tumor necrosis factor-alpha (TNFalpha) release, in vitro and in vivo, was <200 nmol/l. In vivo, SD0006 was effective in the rat streptococcal-cell-wall-induced arthritis model, with dramatic protective effects on paw joint integrity and bone density as shown by radiographic analysis. In the murine collagen-induced arthritis model, equivalence was demonstrated to anti-TNFalpha treatment. SD0006 also demonstrated good oral anti-inflammatory efficacy with excellent cross-species correlation between the rat, cynomolgus monkey, and human. SD0006 suppressed expression of multiple proinflammatory proteins at both the transcriptional and translational levels. These properties suggest SD0006 could provide broader therapeutic efficacy than cytokine-targeted monotherapeutics.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Bone Density; Cell Line; Endotoxemia; Female; Humans; Inflammation; Inflammation Mediators; Lipopolysaccharides; Macaca fascicularis; Male; Mice; Mice, Inbred DBA; Models, Molecular; p38 Mitogen-Activated Protein Kinases; Pain; Pyrazoles; Pyrimidines; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

p38 mitogen-activated protein kinase (p38MAPK) is a critical negative regulator for nucleus pulposus (NP) cell metabolism contributing to intervertebral disc degeneration (IDD). Histone deacetylase 4 (HDAC4) has the ability to mediate cell proliferation and is affected by p38MAPK. It is unclear whether the p38 MAPK inhibitor SD0006 (SD) can regulate IDD. Our study aims to explore the effect of SD in the progression of IDD, as well as its potential mechanism.. NP cells isolating from mild degenerated NP tissues were cultured, and IL-1β or Asiatic acid (AA) was used to activate p38MAPK and accelerate the NP cell degradation. Then, SD was used to reject the p38MAPK activation. After that, the levels of phosphorylated p38MAPK (p-p38), HDAC4, proliferating cell nuclear antigen (PCNA), inflammatory factor, proliferative cell rate, and cell cycle were determined by Western blot, RT-PCR, flow cytometry, and immunofluorescence, respectively.. The results showed that the activation of p38MAPK by IL-1β and AA decreased the HDAC4 expression, affected the collagen-Ⅱ expression, upregulated the TNF-α, IL-6, MMP-3, and ADAMTS mRNA levels, and prevent the NP cell proliferation by mediating cell cycles. However, the application of SD alleviated the negative effect of p-p38 by upregulating HDAC4, anti-inflammation, and promoting cell proliferation, while the blocking of HDAC4 expression partly abolished the effect of SD.. SD can prevent NP cell degeneration by promoting cell proliferation and suppressing inflammation via p38MAPK/HDAC4 pathway.

Topics: Cell Line; Cell Proliferation; Cell Survival; Histone Deacetylases; Humans; Inflammation; Nucleus Pulposus; p38 Mitogen-Activated Protein Kinases; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Repressor Proteins