SAR of 3,4-Dihydropyrido[3,2-d]pyrimidone p38 inhibitors

Liu, Luping; Stelmach, John E.; Natarajan, S.; Chen, Meng-Hsin; Singh, Suresh B.; Schwartz, Cheryl D.; Fitzgerald, Catherine E.; O’Keefe, Stephen J.; Zaller, Dennis M.; Schmatz, Dennis M.; Doherty, James B.

doi:10.1016/j.bmcl.2003.08.059

Cited by 110 publications

(28 citation statements)

References 13 publications

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“…Because both Vertex and Novartis chemical series are identical outside of the sulfur to sulfonamide difference, the loss of activity can be attributed to the differential geometry that sulfonamides adopt. Around this same timeframe, Merck, while acknowledging inspiration form VX-745, also published highly analogous dihydroquinazolinone compounds, in which sp3 character was added to the linker bicycle (compounds 25 and 26) [48,49], where the reported activity was comparable to that of the Vertex series only after an additional substitution was added in the direction of Asp168, and where the predicted binding interactions described above were detailed [49] and shortly thereafter confirmed in their publication of the crystallographic structure [50]. At this time, Merck also published VX-745 dihydroquinazolinone analogues that…”

Section: Different Binding Modes the Teardrop Bindersmentioning

confidence: 96%

MAP Kinase p38Inhibitors: Clinical Results and an Intimate Look at Their Interactions with p38α Protein

Lee¹,

Dominguez

2005

CMC

228

172

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Mitogen-activated protein kinase p38 is a serine/threonine kinase originally isolated from lipopolysaccharide (LPS) stimulated monocytes. There are four isoforms p38alpha p38beta, p38gamma, and p38delta. The most thoroughly studied isoform is p38alpha, whose activation has been observed in many hematopoietic and non-hematopoietic cell types upon appropriate stimuli. Subsequently, p38alpha kinase has been shown to be involved in the biosynthesis of TNFalpha and IL-1beta at the translational and transcriptional level. MAP kinase p38alpha represents a point of convergence for multiple signaling processes that are activated in inflammation and thus a key potential target for the modulation of cytokine production. The discovery and publication of p38alpha and the pyridinyl-imidazole inhibitor initiated a huge effort by many companies to develop p38alpha inhibitors as potential treatment for inflammatory diseases. Herein we provide a brief overview of recent reported clinical results for AMG 548, BIRB 796, VX 702, SCIO 469, and SCIO 323. However, our focus will be on the binding modes of these inhibitors and other p38 inhibitors in the recent literature.

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Section: Different Binding Modes the Teardrop Bindersmentioning

confidence: 96%

MAP Kinase p38Inhibitors: Clinical Results and an Intimate Look at Their Interactions with p38α Protein

Lee¹,

Dominguez

2005

CMC

228

172

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“…dihydroquinazolin-2-ones [86,87], napthyridinones [87], and pyrido[3,2-d]pyrimidin-2-ones [88] have been further disclosed. Introduction of piperidino or piperazino groups in position 7 of the bicyclic scaffold provided improved activity, although these compounds still displayed poor pharmacokinetic properties.…”

Section: Structure-activity Relationships Of P38mentioning

confidence: 98%

Structure-Activity Relationships of p38 Mitogen-Activated Protein Kinase Inhibitors

Bolós

2005

MRMC

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Rheumatoid arthritis and other chronic inflammatory diseases constitute a major therapeutic challenge, usually not sufficiently met by the classical antiinflammatory medications. Recent research efforts provided new insights into the molecular basis of these pathologies and disclosed new opportunities for developing improved drugs directed to the chemical mediators of the disease. The enzyme p38 MAP kinase plays a central role in the signal transduction cascade that leads to the production of both the proinflammatory cytokines, TNF-alpha and IL-1 beta, thus representing an attractive therapeutic target for novel antiinflammatory therapies. A number of p38 inhibitors belonging to different structural families have been developed as potential antiinflammatory drugs, and some of them progressed into clinical trials. The initial pyridinyl imidazole inhibitors contributed to the identification and characterization of p38 MAP kinase as the molecular target of these new drugs, and were found to act as competitive inhibitors at the ATP binding site of the enzyme. A number of variations in the pyridine and imidazole rings were subsequently introduced. Other inhibitors structurally unrelated to the pyridinylimidazoles have also been developed, such as the pyridopyridazinones, diaryl ureas, aminobenzophenones and aromatic amides. One of these structural classes, the N,N'-diarylureas, has been found to interact with a distinct allosteric site of p38 MAP kinase and requires a deep conformational change prior to binding.

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“…11) [71][72][73][74]. Co-crystal structures of several compounds (PDB IDs 1OVE, 1OUY, 1M7Q) revealed the 2,4-difluorophenyl group to be situated in hydrophobic pocket I and the dichlorobenzene ring in hydrophobic region II [75].…”

Section: Merck Analogues Of 37mentioning

confidence: 99%

Successful Structure-Based Design of Recent p38 MAP Kinase Inhibitors

Karcher¹,

Laufer

2009

CTMC

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Inflammation is a complex immune response to cellular and tissue damage caused by physical, chemical, immunological, or microbial stimuli [1]. Prior to the successful launch of the anti-cytokine biologics [2-4], therapeutic approaches for the treatment of chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease were associated with severe side effects. Although biological agents have revolutionized the treatment of inflammatory disorders, the high costs and inconvenient dosing regimens would greatly benefit from novel safe and effective orally active inhibitors of tumor necrosis factor (TNF) alpha and interleukin (IL) 1beta. The clinical benefit of anti-cytokine therapy [5] and the central role of the p38 mitogen-activated protein (MAP) kinase in up-regulation of pro-inflammatory cytokines such as IL-1beta and TNF-alpha [6] suggest that p38 MAP kinase is a promising target for anti-inflammatory therapy [7-14]. Since 1993 an immense number of inhibitors of p38 MAP kinase have been characterized. To date, aside from the well known pyridinylimidazoles, multiple novel scaffolds have been identified, but only a small number have advanced into clinical phase II studies [15], probably due to high toxicity and poor selectivity [16]. To gain safe drug profiles, high potency, marginal CYP450 (cytochrome P450) interaction and toxicity, as well as high levels of selectivity would be desirable. This review will summarize current knowledge on p38 MAP kinase inhibitors and will critically discuss proceedings and strategies toward achieving selectivity and potency.

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SAR of 3,4-Dihydropyrido[3,2-d]pyrimidone p38 inhibitors

Cited by 110 publications

References 13 publications

MAP Kinase p38Inhibitors: Clinical Results and an Intimate Look at Their Interactions with p38α Protein

MAP Kinase p38Inhibitors: Clinical Results and an Intimate Look at Their Interactions with p38α Protein

Structure-Activity Relationships of p38 Mitogen-Activated Protein Kinase Inhibitors

Successful Structure-Based Design of Recent p38 MAP Kinase Inhibitors

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