0000000000337661

AUTHOR

Bozena Frackowiak

showing 4 related works from this author

Design and synthesis of 1-aryl-5-anilinoindazoles as c-Jun N-terminal kinase inhibitors.

2012

Starting from pyrazole HTS hit (1), a series of 1-aryl-1H-indazoles have been synthesized as JNK3 inhibitors with moderate selectivity against JNK1. SAR studies led to the synthesis of 5r as double digital nanomolar JNK3 inhibitor with good in vivo exposure.

IndazolesStereochemistryClinical BiochemistryPharmaceutical SciencePlasma protein bindingPyrazoleBiochemistrychemistry.chemical_compoundStructure-Activity RelationshipIn vivoMitogen-Activated Protein Kinase 10Drug DiscoveryStructure–activity relationshipAnimalsMitogen-Activated Protein Kinase 8Molecular BiologyProtein Kinase InhibitorsAniline CompoundsChemistryKinaseArylOrganic Chemistryc-junJNK Mitogen-Activated Protein KinasesBrainCombinatorial chemistryRatsDrug DesignMolecular MedicineSelectivityHalf-LifeProtein BindingBioorganicmedicinal chemistry letters
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Structure-Activity Relationships and X-ray Structures Describing the Selectivity of Aminopyrazole Inhibitors for c-Jun N-terminal Kinase 3 (JNK3) ove…

2009

c-Jun N-terminal kinase 3alpha1 (JNK3alpha1) is a mitogen-activated protein kinase family member expressed primarily in the brain that phosphorylates protein transcription factors, including c-Jun and activating transcription factor-2 (ATF-2) upon activation by a variety of stress-based stimuli. In this study, we set out to design JNK3-selective inhibitors that had >1000-fold selectivity over p38, another closely related mitogen-activated protein kinase family member. To do this we employed traditional medicinal chemistry principles coupled with structure-based drug design. Inhibitors from the aminopyrazole class, such as SR-3576, were found to be very potent JNK3 inhibitors (IC(50) = 7 nm)…

Models MolecularStereochemistryProtein ConformationPyrazoleCrystallography X-RayBiochemistryp38 Mitogen-Activated Protein Kinaseschemistry.chemical_compoundStructure-Activity RelationshipProtein structureMitogen-Activated Protein Kinase 10Insulin-Secreting CellsStructure–activity relationshipAnimalsHumansEnzyme InhibitorsPhosphorylationProtein kinase AMolecular BiologyCells CulturedIndazolebiologyActivating Transcription Factor 2Active siteCell BiologyActivating transcription factor 2RatschemistryProtein Structure and Foldingbiology.proteinPyrazolesSelectivityJournal of Biological Chemistry
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Structure–activity relationships, and drug metabolism and pharmacokinetic properties for indazole piperazine and indazole piperidine inhibitors of RO…

2007

ROCK has been implicated in many diseases ranging from glaucoma to spinal cord injury and is therefore an important target for therapeutic intervention. In this study, we have designed a series of 1-(4-(1H-indazol-5-yl)piperazin-1-yl)-2-hydroxy(or 2-amino) analogs and a series of 1-(4-(1H-indazol-5-yl amino)piperidin-1-yl)-2-hydroxy(or 2-amino) inhibitors of ROCK-II. SR-1459 has IC50 = 13 nM versus ROCK-II while the IC50s for SR-715 and SR-899 are 80 nM and 100 nM, respectively. Many of these inhibitors, especially the 2-amino substituted analogs for both series, are modest/potent CYP3A4 inhibitors as well. However, a few of these inhibitors (SR-715 and SR-899) show strong selectivity for R…

KinaseIndazolesInhibitorStereochemistryClinical BiochemistryPharmaceutical ScienceProtein Serine-Threonine KinasesPharmacologyBiochemistryPiperazinesInhibitory Concentration 50Structure-Activity Relationshipchemistry.chemical_compoundDrug StabilityPiperidinesIn vivoDrug DiscoveryAnimalsCytochrome P-450 CYP3ACytochrome P-450 Enzyme InhibitorsHumansStructure–activity relationshipPharmacokineticsRho-kinaseProtein Kinase InhibitorsMolecular BiologyCytochrome P-450 Enzyme Inhibitorsrho-Associated KinasesIndazoleCYP3A4Organic ChemistryIntracellular Signaling Peptides and ProteinsROCK-IIRatsPiperazinePharmaceutical PreparationschemistryMolecular MedicinePiperidineDrug metabolismBioorganic & Medicinal Chemistry Letters : a tetrahedron publication for the rapid dissemination of preliminary communication and all aspects of bioorganic chemistry, medicinal chemistry and related disciplines
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The development of benzimidazoles as selective rho kinase inhibitors

2010

Rho Kinase (ROCK) is a serine/threonine kinase whose inhibition could prove beneficial in numerous therapeutic areas. We have developed a promising class of ATP-competitive inhibitors based upon a benzimidazole scaffold, which show excellent potency toward ROCK (IC(50)<10nM). This report details the optimization of selectivity for ROCK over other related kinases such as Protein kinase A (PKA).

Serine/threonine-specific protein kinaserho-Associated KinasesMAP kinase kinase kinaseChemistryKinaseOrganic ChemistryClinical BiochemistryPharmaceutical ScienceGlaucomaChromanMitogen-activated protein kinase kinaseBiochemistryBenzimidazoleBiochemistryDrug DiscoveryROCKMolecular MedicineBenzimidazolesCyclin-dependent kinase 9Protein kinase ARho KinaseProtein Kinase InhibitorsMolecular BiologyRho-associated protein kinaseProtein kinase CBioorganic & Medicinal Chemistry Letters : a tetrahedron publication for the rapid dissemination of preliminary communication and all aspects of bioorganic chemistry, medicinal chemistry and related disciplines
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