0000000000682732

AUTHOR

Thomas Schröter

showing 2 related works from this author

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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