Development of oral renin inhibitors and their clinical applications
| Project/Area Number |
61870036
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| Research Category |
Grant-in-Aid for Developmental Scientific Research
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| Allocation Type | Single-year Grants |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Ehime University |
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Principal Investigator |
KOKUBU Tatsuo Ehime University Professor, 医学部, 教授 (90028324)
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| Co-Investigator(Kenkyū-buntansha) |
TAKADA Yasuharu Ehime University ex-lecturer, 医学部附属病院(元), 講師 (20127898)
NISHIMURA Kazutaka Ehime Univeristy ex-lecturer, 医学部附属病院(元), 講師 (70036482)
SUMIMOTO Takumi Ehime University Associate, 医学部附属病院, 助手 (10187809)
MURAMKAMI Eiki Ehime University Lecturer, 医学部附属病院, 講師 (90110832)
HIWADA Kunio Ehime University Associate Professor, 医学部, 助教授 (00108391)
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| Project Period (FY) |
1986 – 1987
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| Project Status |
Completed (Fiscal Year 1987)
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| Budget Amount *help |
¥4,800,000 (Direct Cost: ¥4,800,000)
Fiscal Year 1987: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1986: ¥3,600,000 (Direct Cost: ¥3,600,000)
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| Keywords | Human renin / Renin inhibitors / Statine / Cyclostatine / Catepsin D / Pepsin / Marmosets / 内服投与 / トリペプチドレニン阻害剤 |
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| Research Abstract |
The renin-angiotensin system plays an improtant role in blood pressure and electrolyte homeostasis. It has been reported that the interruption of the system with angiotensin converting enzyme inhibitor can lower the blood pressure in a large parcentage of essential hypertensive patients. Angiotensin converting enzyme cleaves substrates other than anguotensin I of bradykinin. Thus, it is very attractive to inhibit specifically the initial step in this pathway.
We ara developing oral renin inhibitors which are highly potent, renin-specific, ans long-acting in vivo. We have reported on the statine-containing dipertide and tripeptide inhibitors of human renin. In this project, we synthesized two potent inhibitors of human renin. One is a compound ES-1005 (Bis-naphthylmethylacetyl-His-Sta-lU-lysinol) and the other is a compound ES-6864 (Morphorinocarbonyl-naphthylemethylpropionyl-taiazolyl-Ala-cyclostatione-moepholinoethylamide). ES-1005 is more soulble than ES-6864, but ES-6864 is more absorbable than ES-1005. Both compound were found to be highly potent inhibitors of human renin and competitively inhibited human. Ki values of ES-1005 and ES-6864 were 2.4 x 10-^<-9> M and 7.3 x 10^<-9> M, respectively. ES-1005 had moderate inhibitory potencies against cathepsin D and pepsin (IC50 of cathepsin D and pepsin of 1.6 x 10^<-5> and 8.0 x 10^<-6>M, respectively. However, ES-6864 had no inhibitory potency against cathepsin D and pepsin at a concentration of 10^<-5> M.
Oral administration of ES-6864 at 30 mg/kg to conscious, sodium-depleted matmosets produced a significant blood pressure refuction and almost complete inhibition of PRA that persisted for 5 hours, The dose-related dectrases of blood pressure in the matmosets were observed by oral asministration of ES-6864.
These results opened a new prospect for the development of renin inhibitors that can be used clinically.
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Report
(2 results)
Research Products
(7 results)
