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1.
Toxicol Pathol ; 38(4): 606-18, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20448081

ABSTRACT

Exposure to moderately selective p38alpha mitogen-activated protein kinase (MAPK) inhibitors in the Beagle dog results in an acute toxicity consisting of mild clinical signs (decreased activity, diarrhea, and fever), lymphoid necrosis and depletion in the gut-associated lymphoid tissue (GALT), mesenteric lymph nodes and spleen, and linear colonic and cecal mucosal hemorrhages. Lymphocyte apoptosis and necrosis in the GALT is the earliest and most prominent histopathologic change observed, followed temporally by neutrophilic infiltration and acute inflammation of the lymph nodes and spleen and multifocal mucosal epithelial necrosis and linear hemorrhages in the colon and cecum. These effects are not observed in the mouse, rat, or cynomolgus monkey. To further characterize the acute toxicity in the dog, a series of in vivo, in vitro, and immunohistochemical studies were conducted to determine the relationship between the lymphoid and gastrointestinal (GI) toxicity and p38 MAPK inhibition. Results of these studies demonstrate a direct correlation between p38alpha MAPK inhibition and the acute lymphoid and gastrointestinal toxicity in the dog. Similar effects were observed following exposure to inhibitors of MAPK-activated protein kinase-2 (MK2), further implicating the role of p38alpha MAPK signaling pathway inhibition in these effects. Based on these findings, the authors conclude that p38alpha MAPK inhibition results in acute lymphoid and GI toxicity in the dog and is unique among the species evaluated in these studies.


Subject(s)
Gastrointestinal Diseases/chemically induced , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Lymphatic Diseases/chemically induced , Protein Kinase Inhibitors/toxicity , Protein Serine-Threonine Kinases/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , B-Lymphocytes/metabolism , Blotting, Western , Cell Proliferation/drug effects , Cells, Cultured , Colon/drug effects , Colon/pathology , Dogs , Female , Gastrointestinal Diseases/pathology , Gastrointestinal Hemorrhage/chemically induced , Humans , Immunohistochemistry , Intracellular Signaling Peptides and Proteins/metabolism , Linear Models , Lymph Nodes/drug effects , Lymph Nodes/pathology , Lymphatic Diseases/pathology , Macaca fascicularis , Male , Mice , Protein Serine-Threonine Kinases/metabolism , Rats , Rats, Sprague-Dawley , Spleen/cytology , Spleen/metabolism , T-Lymphocytes/metabolism , Toxicity Tests, Acute , p38 Mitogen-Activated Protein Kinases/metabolism
2.
Bioorg Med Chem Lett ; 20(8): 2634-8, 2010 Apr 15.
Article in English | MEDLINE | ID: mdl-20227876

ABSTRACT

Starting from an initial HTS screening lead, a novel series of C(5)-substituted diaryl pyrazoles were developed that showed potent inhibition of p38alpha kinase. Key to this outcome was the switch from a pyridyl to pyrimidine at the C(4)-position leading to analogs that were potent in human whole blood based cell assay as well as in a number of animal efficacy models for rheumatoid arthritis. Ultimately, we identified a clinical candidate from this substrate; SD-0006.


Subject(s)
Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , Catalytic Domain , Humans , Models, Molecular , p38 Mitogen-Activated Protein Kinases/metabolism
3.
Pharmacology ; 84(1): 42-60, 2009.
Article in English | MEDLINE | ID: mdl-19590255

ABSTRACT

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.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Arthritis, Experimental/drug therapy , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Administration, Oral , Animals , Bone Density/drug effects , Cell Line , Endotoxemia/drug therapy , Endotoxemia/metabolism , Female , Humans , Inflammation/drug therapy , Inflammation/metabolism , Inflammation/physiopathology , Inflammation Mediators/antagonists & inhibitors , Inflammation Mediators/metabolism , Lipopolysaccharides/pharmacology , Macaca fascicularis , Male , Mice , Mice, Inbred DBA , Models, Molecular , Pain/drug therapy , Rats , Rats, Inbred Lew , Rats, Sprague-Dawley , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism
4.
J Pharmacol Exp Ther ; 317(3): 1044-53, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16501068

ABSTRACT

Mitogen-activated protein kinase (MAPK) pathways are implicated in joint destruction in rheumatoid arthritis (RA) by modulating the production and functions of inflammatory cytokines. Although p38 MAPK (p38) participates in signaling cascades leading to osteolysis in arthritis, the mechanisms of its action in this process remain incompletely understood. Here, we found that the osteoclast (Ocl) precursors expressed p38alpha, but not p38beta, p38delta, and p38gamma isoforms. Treatment of these cells with receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) resulted in p38 activation. Importantly, Ocl development induced by RANKL or RANKL and tumor necrosis factor (TNF)-alpha was blocked with the novel p38 inhibitor 4-(3-(4-chlorophenyl)-5-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine (SC-409). To validate in vitro data, p38 role was further investigated in streptococcal cell wall (SCW)-induced arthritis in rats. We found that SCW-induced joint swelling and bone destruction were attenuated by SC-409. Mechanistically, the data show that SCW-stimulated DNA binding activity of the transcription factor myocyte-enhancing factor 2 C, which is downstream of p38, was inhibited by SC-409. In addition, SC-409 inhibited SCW-stimulated expression of numerous factors, including TNF-alpha, interleukin-1beta, and RANKL. Although c-Jun NH2-terminal kinase and NF-kappaB pathways were activated in vitro by RANKL and in vivo by SCW, SC-409 had no significant effect on these pathways. In conclusion, our data show that p38 modulates the production and signaling of cytokines, thus providing a mechanism of the bone-sparing effect of SC-409 in rat arthritis. These data present SC-409 as a novel potent p38 inhibitor and suggest that p38-based therapies may be beneficial in preventing bone loss associated with RA.


Subject(s)
Arthritis, Experimental/prevention & control , Osteoclasts/drug effects , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , Arthritis, Experimental/enzymology , Arthritis, Experimental/pathology , Bones of Lower Extremity/drug effects , Bones of Lower Extremity/enzymology , Bones of Lower Extremity/pathology , Carrier Proteins/pharmacology , Cell Line , Cytokines/biosynthesis , Female , Humans , Membrane Glycoproteins/pharmacology , Mice , Molecular Structure , Osteoclasts/enzymology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , RANK Ligand , Rats , Rats, Inbred Lew , Receptor Activator of Nuclear Factor-kappa B , Signal Transduction/drug effects , Tumor Necrosis Factor-alpha/antagonists & inhibitors
5.
Am J Ther ; 2(9): 648-659, 1995 Sep.
Article in English | MEDLINE | ID: mdl-11854842

ABSTRACT

Prostaglandin E(2) (PGE(2)) is known to inhibit in vitro T-cell responses to mitogenic and antigenic stimuli. Interaction of PGE(2) with a G protein-coupled receptor activates adenylyl cyclase, leading to cAMP formation and inhibition of interleukin-2 (IL-2) production and T-cell proliferation. Despite these effects, the application of PGE(2) as an anti-inflammatory agent has been compromised by its unfavorable pharmacodynamic and side-effect profile. Because of the potential utility of synthetic analogs as prostaglandin-based therapeutics, we evaluated the effect of misoprostol and over 100 structural analogs on cAMP formation and T-cell activation. Our results indicate that micromolar concentrations of misoprostol and particular analogs elicited a rapid and substantial rise in cAMP levels in human peripheral blood mononuclear cells. Analogs which increased cAMP also suppressed IL-2 production and T-cell growth in vitro, whereas those devoid of suppressive activity weakly induced nucleotide synthesis. Despite extensive chemical alteration of the prostanoid structure, no single analog was superior to misoprostol in inducing cAMP or modulating T-cell activity. Misoprostol and suppressive analogs were also evaluated in vivo in a murine model of antigen-induced T-cell proliferation. Prostaglandins, administered at maximum tolerable doses, were ineffective in blocking a T-cell response to alloantigenic stimulation, whereas cyclosporine and prednisolone were potent inhibitors of this response. Overall, our results indicate that misoprostol and related analogs suppress T-cell activation in vitro but require concentrations 1000-fold greater than the low nanomolar plasma levels achieved with clinical doses of misoprostol. Whether misoprostol analogs of sufficient potency can be developed for pharmacologic attentuation of T-cell activation in vivo remains to be determined.

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