Heterocyclic indazole derivatives as SGK1 inhibitors, WO2008138448. 2010

Florian Lang, and Agnes Görlach
Department of Physiology, Eberhard-Karls-University of Tuebingen, Gmelinstrasse 5, D-72076 Tuebingen, Germany. florian.lang@uni-tuebingen.de

Heterocyclic indazole derivatives are claimed in patent WO2008138448 as inhibitors of the serum- and glucocorticoid-inducible-kinase 1 (SGK1) and drugs for the pharmacological treatment of SGK1-related diseases, such as diabetes, obesity, metabolic syndrome, systemic and pulmonary hypertension, cardiac fibrosis, hypertrophy and insufficiency, arteriosclerosis, glomerulosclerosis, nephrosclerosis, nephritis, nephropathy, deranged electrolyte excretion, fibrosing and inflammatory disease (e.g., liver cirrhosis, lung fibrosis, rheumatism, arthrosis, Crohn s disease, chronic bronchitis, radiation fibrosis, sclerodermia, cystic fibrosis, scar formation and Alzheimer' disease), tumor growth, peptic ulcers and some disorders hitherto not conclusively shown to involve SGK1. Most of the claims are supported by the literature. SGK1 is ubiquitously expressed and its expression is stimulated by hyperglycemia, cell shrinkage, ischemia, glucocorticoids, mineralocorticoids and several inflammatory mediators including TGF-ss. SGK1 is activated by insulin and growth factors via the phosphatidylinositol-3-kinase pathway. SGK1 regulates ion channels (including ENaC, KCNE1/KCNQ1), carriers (including NCC, NHE3, SGLT1), Na(+)/K(+)-ATPase, enzymes (including glycogen-synthase-kinase-3) and transcription factors (including FOXO3a, ss-catenin, NF-kappaB). A gain-of-function SGK1 gene variant, carried by approximately 3 - 5% of Caucasians and approximately 10% of Africans, is associated with increased blood pressure, obesity and type 2 diabetes. In vitro and in vivo experiments suggested a critical role of SGK1 in renal fluid retention and hypertension, glucose-induced obesity, coagulation and increased matrix protein formation.

UI MeSH Term Description Entries
D007191 Indazoles A group of heterocyclic aromatic organic compounds consisting of the fusion of BENZENE and PYRAZOLES. Indazole
D010330 Patents as Topic Works about exclusive legal rights or privileges applied to inventions, plants, etc. Trademarks,Patents as Topics,Trademark
D005786 Gene Expression Regulation Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation. Gene Action Regulation,Regulation of Gene Expression,Expression Regulation, Gene,Regulation, Gene Action,Regulation, Gene Expression
D006571 Heterocyclic Compounds Cyclic compounds that include atoms other than carbon in their ring structure. Heterocyclic Compound,Compound, Heterocyclic,Compounds, Heterocyclic
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D016503 Drug Delivery Systems Systems for the delivery of drugs to target sites of pharmacological actions. Technologies employed include those concerning drug preparation, route of administration, site targeting, metabolism, and toxicity. Drug Targeting,Delivery System, Drug,Delivery Systems, Drug,Drug Delivery System,Drug Targetings,System, Drug Delivery,Systems, Drug Delivery,Targeting, Drug,Targetings, Drug
D017346 Protein Serine-Threonine Kinases A group of enzymes that catalyzes the phosphorylation of serine or threonine residues in proteins, with ATP or other nucleotides as phosphate donors. Protein-Serine-Threonine Kinases,Serine-Threonine Protein Kinase,Serine-Threonine Protein Kinases,Protein-Serine Kinase,Protein-Serine-Threonine Kinase,Protein-Threonine Kinase,Serine Kinase,Serine-Threonine Kinase,Serine-Threonine Kinases,Threonine Kinase,Kinase, Protein-Serine,Kinase, Protein-Serine-Threonine,Kinase, Protein-Threonine,Kinase, Serine-Threonine,Kinases, Protein Serine-Threonine,Kinases, Protein-Serine-Threonine,Kinases, Serine-Threonine,Protein Kinase, Serine-Threonine,Protein Kinases, Serine-Threonine,Protein Serine Kinase,Protein Serine Threonine Kinase,Protein Serine Threonine Kinases,Protein Threonine Kinase,Serine Threonine Kinase,Serine Threonine Kinases,Serine Threonine Protein Kinase,Serine Threonine Protein Kinases
D047428 Protein Kinase Inhibitors Agents that inhibit PROTEIN KINASES. Protein Kinase Inhibitor,Inhibitor, Protein Kinase,Inhibitors, Protein Kinase,Kinase Inhibitor, Protein,Kinase Inhibitors, Protein
D017874 Immediate-Early Proteins Proteins that are coded by immediate-early genes, in the absence of de novo protein synthesis. The term was originally used exclusively for viral regulatory proteins that were synthesized just after viral integration into the host cell. It is also used to describe cellular proteins which are synthesized immediately after the resting cell is stimulated by extracellular signals. Proteins, Immediate-Early,Immediate Early Proteins,Proteins, Immediate Early

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