title: The orally active urotensin receptor antagonist, KR36676, attenuates cellular and cardiac hypertrophy.
abstract: OBJECTIVE
  Blockade of the actions of urotensin-II (U-II) mediated by the urotensin (UT) receptor should improve cardiac function and prevent cardiac remodelling in cardiovascular disease. Here, we have evaluated the pharmacological properties of the recently identified UT receptor antagonist, 2-(6,7-dichloro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)-N-methyl-N-(2-(pyrrolidin-1-yl)-1-(4-(thiophen-3-yl)phenyl) ethyl)acetamide (KR36676).
  
  
  METHODS
  Pharmacological properties of KR36676 were studied in a range of in vitro assays (receptor binding, calcium mobilization, stress fibre formation, cellular hypertrophy) and in vivo animal models such as cardiac hypertrophy induced by transverse aortic constriction (TAC) or myocardial infarction (MI).
  
  
  RESULTS
  KR36676 displayed high binding affinity for the UT receptor (Ki : 0.7 nM), similar to that of U-II (0.4 nM), and was a potent antagonist at that receptor (IC50 : 4.0 nM). U-II-induced stress fibre formation and cellular hypertrophy were significantly inhibited with low concentrations of KR36676 (≥0.01 μM). Oral administration of KR36676 (30 mg·kg(-1) ) in a TAC model in mice attenuated cardiac hypertrophy and myocardial fibrosis. Moreover, KR36676 restored cardiac function and myocyte size in rats with MI-induced cardiac hypertrophy.
  
  
  CONCLUSIONS
  A highly potent UT receptor antagonist exerted anti-hypertrophic effects not only in infarcted rat hearts but also in pressure-overloaded mouse hearts. KR36676 could be a valuable pharmacological tool in elucidating the complicated physiological role of U-II and UT receptors in cardiac hypertrophy.
authors.affiliation: Research Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology, Daejeon, Korea; Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Daejeon, Korea.
authors.forename: K S
authors.initials: KS
authors.lastname: Oh
authors.forename: J H
authors.initials: JH
authors.lastname: Lee
authors.forename: K Y
authors.initials: KY
authors.lastname: Yi
authors.forename: C J
authors.initials: CJ
authors.lastname: Lim
authors.forename: S
authors.initials: S
authors.lastname: Lee
authors.forename: C H
authors.initials: CH
authors.lastname: Park
authors.forename: H W
authors.initials: HW
authors.lastname: Seo
authors.forename: B H
authors.initials: BH
authors.lastname: Lee
mesh_terms: D000081:Acetamides / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D000284:Administration, Oral; D000818:Animals; D048588:Benzoxazines / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D006332:Cardiomegaly / Q000188:drug therapy* / Q000473:pathology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005483:Flushing / Q000188:drug therapy; D006801:Humans; D008297:Male; D051379:Mice; D032342:Muscle Cells / Q000187:drug effects / Q000473:pathology; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology; D011869:Radioligand Assay; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D014579:Urotensins / Q000494:pharmacology
chemical_list: D000081:Acetamides; D048588:Benzoxazines; C000607772:KR36676; D043562:Receptors, G-Protein-Coupled; D014579:Urotensins; C473142:Uts2r protein, rat; C029677:urotensin II