1-Phenyl-5-pyrazolyl ureas: potent and selective p38 kinase inhibitors

Dumas, Jacques; Hatoum‐Mokdad, Holia; Sibley, Robert; Riedl, Bernd; Scott, William J.; Monahan, Mary Katherine; Lowinger, Timothy B.; Brennan, Catherine A.; Natero, Reina; Turner, Tiffany M; Johnson, Jeffrey S.; Schoenleber, Robert; Bhargava, Ajay; Wilhelm, Scott M.; Housley, Timothy J; Ranges, Gerald; Shrikhande, Alka

doi:10.1016/s0960-894x(00)00272-9

Cited by 57 publications

(37 citation statements)

References 2 publications

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“…Pyrazole derivatives also acting as anti-angiogenic agents 22 , A3 adenosine receptor antagonists 23 , neuropeptide YY5 receptor antagonists 24 , kinase inhibitor for the treatment of type 2 diabetes, hyperlipidemia, obesity 25 , and thrombopiotinmimetics 26 were reported. Recently, urea derivatives of pyrazoles have been reported as potent inhibitors of p38 kinase 27 . Among the highly marketed COX-2 inhibitors that comprise the pyrazole nucleus, celecoxib is the one which is treated as a safe anti-inflammatory and analgesic agent.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, characterization andin vitroandin vivoanti-inflammatory evaluation of novel pyrazole-based chalcones

Chavan

Adsul

Kotmale

et al. 2014

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of novel pyrazole-based chalcones have been designed, synthesized from 1-methyl-5-(2,4,6-trimethoxyphenyl)-1H-pyrazole (6). The structures of regioisomers 6 and 7 were determined by 2D The newly synthesized compounds were tested for their inhibitory activity against COX-1 and COX-2 using an in vitro cyclooxygenase (COX) inhibition assay. Moreover, they were investigated in vivo for their anti-inflammatory activities using carrageenan-induced rat paw edema model for acute inflammation and cotton pellet-induced granuloma model for chronic inflammation. All the synthesized compounds showed potential to demonstrate anti-inflammatory activities, of particular interest compounds 10i, 10e, 10f, and 10h were found to be potent anti-inflammatory agents.

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Section: Introductionmentioning

confidence: 99%

Design, synthesis, characterization andin vitroandin vivoanti-inflammatory evaluation of novel pyrazole-based chalcones

Chavan

Adsul

Kotmale

et al. 2014

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Strong evidence for this speculation can be gained concomitantly from docking studies wherein, the orientation of P1S substituents towards the solvent region support the hydrophilic environment and presence of Lys53, Arg67 and Glu71 residues that render steric as well as hydrogen-bonding interactions. The aryl ring in P1S region is reported to exhibit p-CH 2 interaction with side chain of Glu71 and stabilizes its orientation [24]. In addition to this we have noticed another interaction with Lys53 where the side chain NH 3 + demonstrated a cation-p interaction with the phenyl ring (6-7 Å ).…”

Section: Discussionmentioning

confidence: 55%

“…Dataset and molecular modeling A series of 48 pyrazolyl urea analogues have been selected from the literature to derive CoMFA and CoMSIA models, the structures and their p38 kinase inhibitory activities are listed in Table 1 [24,25]. The activities of the dataset were distributed with in a range of 11-800 nM (approx.…”

Section: Methodsmentioning

confidence: 99%

“…In the present study, we have selected a set of N-pyrazolyl urea derivatives that have been reported as potent and selective p38 kinase inhibitors in biochemical and cellular assays [24,25]. These pyrazolyl urea inhibitors are structurally distinct from the traditional pyridinyl/pyrimidinyl imidazole inhibitors and have also been demonstrated the p38 kinase inhibition by a different mechanism.…”

Section: Introductionmentioning

confidence: 99%

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Strategies to design pyrazolyl urea derivatives for p38 kinase inhibition: a molecular modeling study

Kulkarni

Srivani

Garlapati

et al. 2007

J Comput Aided Mol Des

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The p38 protein kinase is a serine-threonine mitogen activated protein kinase, which plays an important role in inflammation and arthritis. A combined study of 3D-QSAR and molecular docking has been undertaken to explore the structural insights of pyrazolyl urea p38 kinase inhibitors. The 3D-QSAR studies involved comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA). The best CoMFA model was derived from the atom fit alignment with a cross-validated r (2 )(q (2)) value of 0.516 and conventional r (2) of 0.950, while the best CoMSIA model yielded a q (2) of 0.455 and r (2) of 0.979 (39 molecules in training set, 9 molecules in test set). The CoMFA and CoMSIA contour maps generated from these models provided inklings about the influence of interactive molecular fields in the space on the activity. GOLD, Sybyl (FlexX) and AutoDock docking protocols were exercised to explore the protein-inhibitor interactions. The integration of 3D-QSAR and molecular docking has proffered essential structural features of pyrazolyl urea inhibitors and also strategies to design new potent analogues with enhanced activity.

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“…Whereas the tert-butyl group on the heterocyclic ring is essential for the potency in this family of p38 inhibitors, the pyrazole nucleus can be replaced with some other fivemembered heterocycles, such as isoxazoles and thiophenes [93,95]. Improvement of the potency was further achieved by replacement of the pyrazole N-methyl substituent with various aryl groups [94,96]. Alternatively, modifications of the urea N-phenyl ring revealed that this group cannot be successfully replaced for H, cycloalkyl or pyridinyl groups, whereas a naphthyl moiety brought about improved inhibition of p38 in both in vitro and cellular assays [94].…”

Section: Nn'-diarylureasmentioning

confidence: 99%

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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1-Phenyl-5-pyrazolyl ureas: potent and selective p38 kinase inhibitors

Cited by 57 publications

References 2 publications

Design, synthesis, characterization andin vitroandin vivoanti-inflammatory evaluation of novel pyrazole-based chalcones

Design, synthesis, characterization andin vitroandin vivoanti-inflammatory evaluation of novel pyrazole-based chalcones

Strategies to design pyrazolyl urea derivatives for p38 kinase inhibition: a molecular modeling study

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

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