Synthesis and pharmacological characterization of a potent, orally active p38 kinase inhibitor

Dumas, Jacques; Hatoum‐Mokdad, Holia; Sibley, Robert; Smith, Roger A.; Scott, William J.; Khire, Uday R.; Lee, Wendy; Wood, Jill E.; Wolanin, Donald J.; Cooley, Jeffrey; Bankston, Donald; Redman, Anikó M.; Schoenleber, Robert; Caringal, Yolanda; Gunn, David; Romero, Romulo H.; Osterhout, Martin H.; Paulsen, Holger; Housley, Timothy J; Wilhelm, Scott M.; Pirro, John P.; Chien, Du-Shieng; Ranges, Gerald; Shrikhande, Alka; Muzsi, Andrew; Bortolon, Elizabeth; Wakefield, Jean A.; Ostravage, Cynthia Gianpaolo; Bhargava, Ajay; Chau, T. T.

doi:10.1016/s0960-894x(02)00238-x

Cited by 24 publications

(21 citation statements)

References 5 publications

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“…Closer look at the binding orientations of these molecules have revealed that the 6.00 6.25 6.50 6.75 7.00 7. 25 [36][37][38] with polar substituents have exhibited comparatively lower activities. Thus we can infer from this analysis that the P1S pocket possesses two different types of environments, liphophilic and hydrophilic and only those groups which utilize these two regions effectively add to the activity and results in potent inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…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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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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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“…His-tagged-TRAIL was synthesized via plasmid expression as previously described (40) and purification and stored as a 1 mg/ml stock in dPBS at -20˚C. Sorafenib was synthesized in powder, free base form for use in our laboratory as previously described (41). Sorafenib was dissolved in 100% DMSO and stored at -20˚C as a concentrated stock for in vitro studies.…”

Section: Methodsmentioning

confidence: 99%

FLT-PET may not be a reliable indicator of therapeutic response in p53-null malignancy

et al. 2011

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Abstract. FDG (18 F-deoxy-glucose) is the current gold standard for PET imaging. 18 F-fluorothymidine), a PET imaging marker of proliferation, has been proposed as an alternative to FDG for the assessment of therapeutic response. We examined the therapeutic predictive value of FLT-PET and FDG-PET using CALU-6, a human, p53-null, non-small cell lung cancer cell line with comparison of combined targeted therapy, TRAIL and sorafenib, versus combined conventional chemotherapy, docetaxel and cisplatin. CALU-6 tumor-bearing nu/nu mice (n=46) were evaluated in 3 therapeutic trials measuring FLT and FDG prediction of tumor response at 72 h following initiation of daily combination therapy with targeted agents, TRAIL (200 µg i.v.) and sorafenib (30 mg/kg i.p.) and compared to conventional chemotherapeutics cisplatin (3 mg/ kg i.p.) and docetaxel (7.5 mg/kg i.p.). PET imaging response was compared to morphological and histological indicators of therapeutic response, including decreased vascu larity (in vivo AngioSense imaging and anti-CD31 staining), slowed tumor growth (caliper measurements), decreased cellular proliferation (Ki-67 staining) and increased apoptosis (TUNEL staining). Decreases in tumor accumulation of FLT (FLT MAX -30%, p=0.03) at 72 h post treatment were observed in response to TRAIL and sorafenib combination therapy resulting in smaller, less vascular, more apoptotic tumors. No similar reduction in tumor accumulation of FLT (FLT MAX -2%, p=0.67) was observed 72 h following initiation of cisplatin and docetaxel combination therapy, despite histological and morphological evidence of drug response. In contrast, tumor imaging with FDG did demonstrate a decrease in accumulation in both treatment groups, -21% (p=0.30) in response to cisplatin/ docetaxel and -8% (p=0.59) in response to TRAIL/sorafenib, but did not reach statistical significance. FLT, but not FDG, is predictive of therapeutic response to the targeted regimen TRAIL/sorafenib. However, FLT-PET may not predict therapeutic response to DNA damaging agents in p53-null tumors, likely due to loss of cell cycle control of thymidine kinase 1 (TK1). Thus, tumor imaging response by FLT may be limited in human tumors without functional p53.

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“…Structure-activity relationships (SAR) for many amide and urea p38 inhibitors have been published [12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

5-Amino-2-carbonylthiophene derivatives for use as p38 MAPK inhibitors in the treatment of inflammatory diseases

Boehm

2005

Expert Opinion on Therapeutic Patents

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Synthesis and pharmacological characterization of a potent, orally active p38 kinase inhibitor

Cited by 24 publications

References 5 publications

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

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

FLT-PET may not be a reliable indicator of therapeutic response in p53-null malignancy

5-Amino-2-carbonylthiophene derivatives for use as p38 MAPK inhibitors in the treatment of inflammatory diseases

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