A novel urotensin II receptor antagonist, KR-36996, improved cardiac function and attenuated cardiac hypertrophy in experimental heart failure.
Urotensin II and its receptor are thought to be involved in various cardiovascular diseases such as heart failure, pulmonary hypertension and atherosclerosis. Since the regulation of the urotensin II/urotensin II receptor offers a great potential for therapeutic strategies related to the treatment of cardiovascular diseases, the study of selective and potent antagonists for urotensin II receptor is more fascinating. This study was designed to determine the potential therapeutic effects of a newly developed novel urotensin II receptor antagonist, N-(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)benzo[b]thiophene-3-carboxamide (KR-36996), in experimental models of heart failure. KR-36996 displayed a high binding affinity (Ki=4.44±0.67nM) and selectivity for urotensin II receptor. In cell-based study, KR-36996 significantly inhibited urotensin II-induced stress fiber formation and cellular hypertrophy in H9c2UTcells. In transverse aortic constriction-induced cardiac hypertrophy model in mice, the daily oral administration of KR-36996 (30mg/kg) for 14 days significantly decreased left ventricular weight by 40% (P<0.05). In myocardial infarction-induced chronic heart failure model in rats, repeated echocardiography and hemodynamic measurements demonstrated remarkable improvement of the cardiac performance by KR-36996 treatment (25 and 50mg/kg/day, p.o.) for 12 weeks. Moreover, KR-36996 decreased interstitial fibrosis and cardiomyocyte hypertrophy in the infarct border zone. These results suggest that potent and selective urotensin II receptor antagonist could efficiently attenuate both cardiac hypertrophy and dysfunction in experimental heart failure. KR-36996 may be useful as an effective urotensin II receptor antagonist for pharmaceutical or clinical applications.
Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Daejeon 34113, Republic of Korea.
Kwang-Seok
KS
Oh
Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Daejeon 34113, Republic of Korea.
Jeong Hyun
JH
Lee
Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Daejeon 34113, Republic of Korea; Center for Medicinal Chemistry, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
Kyu Yang
KY
Yi
Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Daejeon 34113, Republic of Korea; Center for Medicinal Chemistry, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
Chae Jo
CJ
Lim
Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, Republic of Korea.
Byung Kil
BK
Park
Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
Ho Won
HW
Seo
Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, Republic of Korea. Electronic address: bhlee@krict.re.kr.
Byung Ho
BH
Lee
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D006332:Cardiomegaly / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002460:Cell Line; D002908:Chronic Disease; D004562:Electrocardiography; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology*; D006333:Heart Failure / Q000150:complications*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D011312:Pressure / Q000009:adverse effects; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013379:Substrate Specificity; D013876:Thiophenes / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity
C000617862:KR-36996; D010880:Piperidines; D043562:Receptors, G-Protein-Coupled; D013876:Thiophenes; C512325:urotensin II receptor, mouse
Heart failure; Hypertrophy; KR-36996; Urotensin II receptor antagonist