title: EMD638683, a novel SGK inhibitor with antihypertensive potency.
abstract: The serum- and glucocorticoid-inducible kinase 1 (SGK1) is transcriptionally upregulated by mineralocorticoids and activated by insulin. The kinase enhances renal tubular Na(+)-reabsorption and accounts for blood pressure increase following high salt diet in mice made hyperinsulinemic by dietary fructose or fat. The present study describes the in vitro and in vivo efficacy of a novel SGK1 inhibitor (EMD638683). EMD638683 was tested in vitro by determination of SGK1-dependent phosphorylation of NDRG1 (N-Myc downstream-regulated gene 1) in human cervical carcinoma HeLa-cells. In vivo EMD638683 (4460 ppm in chow, i.e. approx. 600 mg/kg/day) was administered to mice drinking tap water or isotonic saline containing 10% fructose. Blood pressure was determined by the tail cuff method, and urinary electrolyte (flame photometry) concentrations determined in metabolic cages. In vitro testing disclosed EMD638683 as a SGK1 inhibitor with an IC50 of 3 μM. Within 24 hours in vivo EMD638683 treatment significantly decreased blood pressure in fructose/saline-treated mice but not in control animals or in SGK1 knockout mice. EMD638683 failed to alter the blood pressure in SGK1 knockout mice. Following chronic (4 weeks) fructose/high salt treatment, additional EMD638683 treatment again decreased blood pressure. EMD638683 thus abrogates the salt sensitivity of blood pressure in hyperinsulinism without appreciably affecting blood pressure in the absence of hyperinsulinism. EMD638683 tended to increase fluid intake and urinary excretion of Na(+), significantly increased urinary flow rate and significantly decreased body weight.
  
  
  CONCLUSIONS
  EMD638683 could serve as a template for drugs counteracting hypertension in individuals with type II diabetes and metabolic syndrome.
authors.affiliation: Department of Physiology, University of Tübingen, Tübingen, Germany.
authors.forename: Teresa F
authors.initials: TF
authors.lastname: Ackermann
authors.forename: Krishna M
authors.initials: KM
authors.lastname: Boini
authors.forename: Norbert
authors.initials: N
authors.lastname: Beier
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Scholz
authors.forename: Thomas
authors.initials: T
authors.lastname: Fuchss
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D005632:Fructose / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D006834:Hydrazines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006973:Hypertension / Q000188:drug therapy; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012964:Sodium / Q000652:urine; D012965:Sodium Chloride / Q000494:pharmacology; D000099184:Serum-Glucocorticoid Regulated Kinases; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D000959:Antihypertensive Agents; D001549:Benzamides; D018797:Cell Cycle Proteins; D005632:Fructose; D006834:Hydrazines; D017874:Immediate-Early Proteins; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D012964:Sodium; D012965:Sodium Chloride; D000099184:Serum-Glucocorticoid Regulated Kinases; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C569030:EMD 638683