Learnings from previous Roche p38-selective inhibitors were applied to a new fragment hit, which was optimized to a potent, exquisitely selective preclinical lead with a good pharmacokinetic profile.

The development of a new series of p38α inhibitors resulted in the identification of two clinical candidates, one of which was advanced into a phase 2 clinical study for rheumatoid arthritis. The original lead, an lck inhibitor that also potently inhibited p38α, was a screening hit from our kinase inhibitor library. This manuscript describes the optimization of the lead to p38-selective examples with good pharmacokinetic properties.

Methotrexate alone or in combination with other agents is the standard treatment for moderate-to-severe rheumatoid arthritis. As biological agents are expensive, they are not usually used until methotrexate has failed to give a good response. Thus, there is scope for the development of cheaper drugs that can be used instead of methotrexate or in addition to methotrexate. Pamapimod is a p38α inhibitor being developed for use in the treatment of rheumatoid arthritis. The objective of this review was to evaluate the recent clinical trials of pamapimod in subjects with rheumatoid arthritis. There is no clear-cut evidence that pamapimod alone or in the presence of methotrexate is efficacious in subjects with rheumatoid arthritis but it does cause adverse effects. It is unlikely that pamapimod will be useful in the treatment of rheumatoid arthritis.

Decades of signal transduction research have elucidated a complex and dynamic architecture of signaling pathways and networks that are associated with cellular responses, physiological responses as well as various pathologies. Consequently, there is great interest in pharmacological manipulation of these pathways for therapeutic purposes. Pathway complexity brings forth two distinct challenges, one in the systematic generation of pathway-level datasets under multiple conditions and one in the interpretation of such complex data. Mechanistic model-based analysis has been used to aid in drug discovery and development, specifically in understanding and predicting the interaction of small molecule inhibitors with pathways. Examples including the quantitative comparison of multiple compounds and mechanisms of action, target selection and the elucidation of clinical findings are reviewed.

HASH(0x2b60a7061fa0)

The classical role of p38MAPK involves the transmission of death signals from stress stimuli such as ionizing radiation, inflammation and chemotherapy in normal and malignant cells. However emerging evidence point to it having pleiotropic functions, ranging from cellular proliferation and survival, to cell cycle arrest and regulation of the tumor microenviroment. The mechanisms responsible for these diverse and rather contradictory functions of p38MAPK are only now being unraveled. In some hematological malignancies, p38MAPK is constitutively activated. The reasons for this are not fully understood, but can result from underlying genetic lesions such as the bcr/abl translocation. The involvement of p38MAPK in mediating cell cycle arrest in the face of cytotoxic damage suggests that p38MAPK may be a therapeutic target. The role of p38MAPK in cytokine production by the stromal compartment adds another level of complexity to the regulation of hematological malignancies that exhibit a degree of stromal dependence, at least some of which is cytokine driven. p38MAPK dependent cytokine production by malignant hematopoietic cells has also been observed, and promotes tumor cell adhesion, angiogenesis and osteoclastogenesis. This suggests a mutual relationship between tumor and stromal cells. In contrast, p38MAPK is required for the effects of cytotoxic agents in some hematological malignancies. These conflicting qualities point to the importance of careful consideration of the use of p38MAPK inhibitors as a therapeutic strategy.

Rheumatoid arthritis (RA) remains a significant unmet medical need despite significant therapeutic advances. The pathogenesis of RA is complex and includes many cell types, including T cells, B cells, and macrophages. Fibroblast-like synoviocytes (FLS) in the synovial intimal lining also play a key role by producing cytokines that perpetuate inflammation and proteases that contribute to cartilage destruction. Rheumatoid FLS develop a unique aggressive phenotype that increases invasiveness into the extracellular matrix and further exacerbates joint damage. Recent advances in understanding the biology of FLS, including their regulation regulate innate immune responses and activation of intracellular signaling mechanisms that control their behavior, provide novel insights into disease mechanisms. New agents that target FLS could potentially complement the current therapies without major deleterious effect on adaptive immune responses.

PURPOSE OF REVIEW: Due to the cost and parenteral mode of administration of biologics, efforts to develop oral small molecule inhibitors to protein kinases involved in cellular signaling that impact inflammatory cytokine production have been ongoing. This article will review the recent publications on these efforts. RECENT FINDINGS: On preclinical work, p38 mitogen-activated kinases were considered attractive targets to suppress cytokine production. Three different molecules (SCIO_469, Pamapimod, VX-702) that target the p38alpha isoform have been evaluated in phase 2 trials. Unfortunately, clinical efficacy was not observed, and dose-related toxicity was seen. The future of this approach is unclear. Targeting more upstream protein tyrosine kinases such as spleen tyrosine kinase (SyK) and the JAK family of kinases has been associated with greater success in clinical trials, with efficacy demonstrated. Adverse events occurred in a dose-dependent fashion with the SyK inhibitor, such as diarrhea and hypertension. Neutropenia, elevated liver-function tests, serum creatinine elevations and lipid elevations have occurred with JAK-kinase inhibition. Dose modifications have been made based on the phase 2 trial results; phase 3 clinical trials are ongoing. SUMMARY: Inhibiting downstream proteins involved in cellular signaling, such as p38, has not been successful to date. Inhibitors of more upstream protein-tyrosine kinases involved in cellular signaling appear to be viable molecular candidates for rheumatoid arthritis. If the results seen in phase 2 studies are confirmed in larger phase 3 studies, we may soon have new, oral DMARD therapies available.

This study evaluated the potential pharmacokinetic interaction of pamapimod, a p38 mitogen-activated protein kinase inhibitor, and methotrexate (MTX) when administered concomitantly in patients with rheumatoid arthritis (RA); the study also evaluated the pharmacodynamic effects of pamapimod. Twenty-two RA patients on a stable regimen of MTX (10-25 mg/wk; administered on days 1 and 8) were randomized to receive 300 mg of pamapimod (n = 17) or placebo (n = 5) once daily (qd) for 10 days (days 5-14). Blood and urine samples were collected pre-and postdose on days 1 (MTX alone), 7 (pamapimod alone), and 8 (MTX and pamapimod coadministered). No clinically significant changes were observed in plasma exposures and renal clearance of pamapimod, MTX, or their metabolites, whether administered separately or concomitantly. The combination of pamapimod (300 mg qd) for 10 days and weekly MTX was generally well tolerated. Parameters of RA disease-namely, tender joint count, swollen joint count, erythrocyte sedimentation rate, and C-reactive protein-generally decreased between days 5 and 14. The results of this study suggest that dose adjustments for either drug are not necessary when concomitantly administered and that pamapimod can decrease pharmacodynamic markers of disease activity.