Jerry Leroy Adams

Inhibition of p38 MAP kinase as a therapeutic strategy

Since the discovery of p38 MAP kinase in 1994, our understanding of its biology has progressed dramatically. The key advances include (1) identification of p38 MAP kinase homologs and protein kinases that act upstream and downstream from p38 MAP kinase, (2) identification of interesting and potentially important substrates, (3) elucidation of the role of p38 MAP kinase in cellular processes and (4) the establishment of the mechanism by which the pyridinylimidazole p38 MAP kinase inhibitors inhibit enzyme activity. It is now known that there are four members of the p38 MAP kinase family. They differ in their tissue distribution, regulation of kinase activation and subsequent phosphorylation of downstream substrates. They also differ in terms of their sensitivities toward the p38 MAP kinase inhibitors. The best-studied isoform is p38 alpha, whose activation has been observed in many hematopoietic and non-hematopoietic cell types upon treatment with appropriate stimuli. The pyridinylimidazole compounds, exemplified by SB 203580, were originally prepared as inflammatory cytokine synthesis inhibitors that subsequently were found to be selective inhibitors of p38 MAP kinase. SB 203580 inhibits the catalytic activity of p38 MAP kinase by competitive binding in the ATP pocket. X-ray crystallographic studies of the target enzyme complexed with inhibitor reinforce the observations made from site-directed mutagenesis studies, thereby providing a molecular basis for understanding the kinase selectivity of these inhibitors. The p38 MAP kinase inhibitors are efficacious in several disease models, including inflammation, arthritis and other joint diseases, septic shock, and myocardial injury. In all cases, p38 activation in key cell types correlated with disease initiation and progression. Treatment with p38 MAP kinase inhibitors attenuated both p38 activation and disease severity. Structurally diverse p38 MAP kinase inhibitors have been tested extensively in preclinical studies.

p38 Mitogen-Activated Protein Kinase Inhibitors— Mechanisms and Therapeutic Potentials

The pyridinylimidazole compounds, exemplified by SB 203580, originally were prepared as inflammatory cytokine synthesis inhibitors. Subsequently, the compounds were found to be selective inhibitors for p38 mitogen-activated protein kinase (MAPK), a member of the MAPK family. SB 203580 inhibits the catalytic activity of p38 MAPK by competitive binding in the ATP pocket. Four homologues of p38 MAPK have been identified to date, and interestingly, their biochemical properties and their respective sensitivities to the inhibitors are distinct. X-ray crystallographic analysis of p38-inhibitor complexes reinforces the observations made from site-directed mutagenesis studies, thereby providing a molecular basis for understanding the kinase selectivity of these inhibitors. The p38 MAPK inhibitors are efficacious in several disease models, including inflammation, arthritis and other joint diseases, septic shock, and myocardial injury.

Disease-modifying activity of SB 242235, a selective inhibitor of p38 mitogen-activated protein kinase, in rat adjuvant-induced arthritis

OBJECTIVE To evaluate the effects of SB 242235, a potent and selective inhibitor of p38 mitogen-activated protein (MAP) kinase, on joint integrity in rats with adjuvant-induced arthritis (AIA). METHODS Male Lewis rats with AIA were orally treated either prophylactically (days 0-20) or therapeutically (days 10-20) with SB 242235. Efficacy was determined by measurements of paw inflammation, dual-energy x-ray absorptiometry for bone-mineral density (BMD), magnetic resonance imaging (MRI), microcomputed tomography (CT), and histologic evaluation. Serum tumor necrosis factor alpha (TNFalpha) in normal (non-AIA) rats and serum interleukin-6 (IL-6) levels in rats with AIA were measured as markers of the antiinflammatory effects of the compound. RESULTS SB 242235 inhibited lipopolysaccharide-stimulated serum levels of TNFalpha in normal rats, with a median effective dose of 3.99 mg/kg. When SB 242235 was administered to AIA rats prophylactically on days 0-20, it inhibited paw edema at 30 mg/kg and 10 mg/kg per day by 56% and 33%, respectively. Therapeutic administration on days 10-20 was also effective, and inhibition of paw edema was observed at 60, 30, and 10 mg/kg (73%, 51%, and 19%, respectively). Significant improvement in joint integrity was demonstrated by showing normalization of BMD and also by MRI and micro-CT analysis. Protection of bone, cartilage, and soft tissues was also shown histologically. Serum IL-6 levels were decreased in AIA rats treated with the 60 mg/kg dose of compound. CONCLUSION Symptoms of AIA in rats were significantly reduced by both prophylactic and therapeutic treatment with the p38 MAP kinase inhibitor, SB 242235. Results from measurements of paw inflammation, assessment of BMD, MRI, and micro-CT indicate that this compound exerts a protective effect on joint integrity, and thus appears to have disease-modifying properties.

Constitutive cyclooxygenase (COX‐1) and inducible cyclooxygenase (COX‐2): Rationale for selective inhibition and progress to date

While a great deal has been discovered concerning the potential physiological and pathological role of prostanoids, much is left to be determined. The widespread distribution of both COX-1 and COX-2 coupled with the capacity of most vascular beds, smooth muscle, as well as leukocytes to respond to prostanoids make drawing generalities difficult. The problems with the majority of currently used NSAIDs are clear and ulcerogenic liability is of obvious concern. Interestingly enough, the mechanism of that damage is still the subject of controversy as illustrated by the recent review and hypothesis of Somasundaram et al. In this treatise, the suggestion is made that the initial gastric damage is the result of uncoupling of oxidative phosphorylation which is independent but simultaneous with COX inhibition. At least two currently marketed NSAIDs have improved G.I. liability (nabumetone and etodolac) with efficacy equivalent to other more ulcerogenic NSAIDs. These drugs appear to have achieved that by a mechanism distinct from selective inhibition of COX-2. Whether or not selective COX-2 inhibitors will demonstrate an improved profile over these compounds remains to be shown. Unfortunately, clinical experience with nimsulide and CGP 28238 suggest that NSAID-like toxicity may still be an issue. The promise of selective COX-2 inhibitors remains largely untested. It is with great interest and expectation that the clinical evaluation of the more selective compounds of different structural types is awaited.

Regulation of stress-induced cytokine production by pyridinylimidazoles; inhibition of CSBP kinase

Members of three classes of pyridinylimidazoles bind with varying affinities to CSBP (p38) kinase which is a member of a stress-induced signal transduction pathway. Based upon SAR and protein homology modeling, the pharmacophore and three potential modes of binding to the enzyme are presented. For a subset of pyridinylimidazoles, binding is shown to correlate with inhibition of CSBP kinase activity, whereas no significant inhibition of PKA, PKC alpha and ERK kinase activity is observed.

p38 MAP kinase: molecular target for the inhibition of pro-inflammatory cytokines.

Publisher Summary This chapter discusses that the network of immune and inflammatory responses is comprised of a variety of cell types. Coordination of this network occurs through both direct cell–cell contact and by way of intercellular signalling molecules. These signalling molecules regulate the growth, differentiation and function of a variety of target cells. Understanding the structure and function of these molecules has provided new and important insights into the fundamental biology of immunity and inflammation, and has led to the identification of new strategies for the development of more effective medicines for the treatment of a variety of autoimmune and inflammatory diseases. The chapter reviews that the pluripotent pro-inflammatory cytokines, interleukin-1 (IL-1), and tumor necrosis factor alpha (TNFα) appear to play particularly important roles in disease. Although, these proteins and their cellular receptors are structurally unrelated, they elicit a similar profile of pro-inflammatory responses. Because IL-1 and TNF are produced early in response to pro-inflammatory signals, and because of their central role in mediating this response, they have often been termed the master cytokines. While the success of these therapies has validated the importance of IL-1 and TNF in promoting disease, they also highlight the need for improved therapies that do not suffer from the disadvantages of proteinaceous macromolecules, which must be administered parenterally and are inherently more expensive to produce than small molecule drugs. To date, no orally active low molecular weight cytokine receptor antagonist has emerged from clinical trials. However, in the last decade several new strategies to interrupt the synthesis and signalling of these cytokines have emerged. One of the first of these targets to be elucidated is the stress-activated protein kinase, p38.

2,4,5- triarylimidazole inhibitors of IL-1 biosynthesis

Abstract As part of an effort to define the pharmacophore and discover the mechanism by which the antiinflammatory dual cyclooxygenase / 5-lipoxygenase inhibitors SK&F 86002 and SK&F 105809 inhibit IL-1 biosynthesis, a series of substituted 2,4,5-triarylimidazole derivatives were prepared and evaluated as inhibitors of IL-1 and 5-lipoxygenase biosynthesis.

Pyrimidinylimidazole inhibitors of CSBP/P38 kinase demonstrating decreased inhibition of hepatic cytochrome P450 enzymes

Pyrimidine analogs of the pyrimidinylimidazole class of CSBP/p38 kinase inhibitors were prepared in an effort to reduce the potent inhibition of hepatic cytochrome P450 observed for the pyridinyl compounds. The substitution of pyrimidin-4-yl, 2-methoxypyrimidin-4-yl, or 2-methylaminopyrimidin-4-yl for pyridin-4-yl effectively dissociates CSBP/p38 kinase from P450 inhibition for this series and furthermore achieves an increase in oral activity.

New inhibitors of p38 kinase

In the short time since the 1994 report that the molecular target for the 4-aryl-5-pyridin-4-yl imidazole class of cytokine suppressive anti-inflammatory agents (exemplified by SB-203580) was the human homologue of the stress-induced kinase p38, there has been an explosion of patent literature disclosing related inhibitor analogues. These compounds fall into the general structural class of vicinal aryl/pyridin-4-yl heterocycles. Compounds of this class have been claimed as p38 inhibitors or inhibitors of cytokine biosynthesis. Since cytokines mediate a variety of disease processes, inhibition of cytokine biosynthesis has potential as a therapeutic target. The SAR of binding to p38 for this intensively studied class of compounds is now understandable on the basis of recent x-ray crystallographic and mutagenesis studies. The inhibitors can be sub-classified based upon a variety of structural characteristics. Recently new inhibitor structural classes have been disclosed. Although distinctly different structurally, several of these new compounds appear to bind with the same key interactions as the vicinal aryl/pyridin-4-yl heterocycles.

Phosphorus-containing purines and pyrimidines: A new class of transition state analogs

Abstract Synthetic routes to the [1,5,2]-diazaphosphorine (“4-phosphapyrimidine”), imidazo[4,5-e][1,5,2]-diazaphosphorine (“6-phosphapurine”), and imidazo[4,5-d][1,3,2]-diazaphosphorine (“2-phosphapurine”) ring systems have been developed. Appropriately functionalized derivatives of these heterocycles are desired as possible transition state analogs of the nucleoside deaminases.