학술논문
Discovery of Novel 2-Carbamoyl Morpholine Derivatives as Highly Potent and Orally Active Direct Renin Inhibitors.
Document Type
Academic Journal
Author
Iijima D; Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.; Sugama H; Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.; Awai N; Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.; Takahashi Y; Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.; Togashi Y; Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.; Takebe T; Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.; Xie J; Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Building 5, No. 898 Halei Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai 201203, PR China.; Shen J; Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Building 5, No. 898 Halei Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai 201203, PR China.; Ke Y; Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Building 5, No. 898 Halei Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai 201203, PR China.; Akatsuka H; Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.; Kawaguchi T; Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.; Takedomi K; Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.; Kashima A; Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.; Nishio M; Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.; Inui Y; Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.; Yoneda H; Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.; Xia G; Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Building 5, No. 898 Halei Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai 201203, PR China.; Iijima T; Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.; Lead Exploration Unit, Drug Discovery Initiative, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Source
Publisher: American Chemical Society Country of Publication: United States NLM ID: 101521073 Publication Model: eCollection Cited Medium: Print ISSN: 1948-5875 (Print) Linking ISSN: 19485875 NLM ISO Abbreviation: ACS Med Chem Lett Subsets: PubMed not MEDLINE
Subject
Language
English
ISSN
1948-5875
Abstract
The renin-angiotensin-aldosterone system (RAAS) plays a key role in the regulation of blood pressure. Renin, the first and rate-limiting enzyme of the RAAS, is an attractive target for the treatment of hypertension and cardiovascular/renal diseases. Therefore, various direct renin inhibitors (DRIs) have been researched over recent decades; however, most exhibited poor pharmacokinetics and oral bioavailability due to the peptidomimetic or nonpeptidomimetic structures with a molecular weight (MW) of >600, and only aliskiren is approved. This study introduces a novel class of DRIs comprised of a 2-carbamoyl morpholine scaffold. These compounds have a nonpeptidomimetic structure and a MW of <500. The representative compound 26 was highly potent despite not occupying S1'-S2' sites or the opened flap region used by other DRIs and exerted a significant antihypertensive efficacy via oral administration on double transgenic mice carrying both the human angiotensinogen and the human renin genes.
Competing Interests: The authors declare the following competing financial interest(s): D.I., H.S., N.A., Y.T., Y.T., T.T., H.A., T.K., K.T., A.K., M.N., Y.I., H.Y. and T.I. were employed by Mitsubishi Tanabe Pharma Corporation at the time this work was done; J.X., J.S., Y.K. and G.X. were employed by Shanghai Pharmaceuticals Holding Co., Ltd. at the time this work was done.
(© 2022 American Chemical Society.)
Competing Interests: The authors declare the following competing financial interest(s): D.I., H.S., N.A., Y.T., Y.T., T.T., H.A., T.K., K.T., A.K., M.N., Y.I., H.Y. and T.I. were employed by Mitsubishi Tanabe Pharma Corporation at the time this work was done; J.X., J.S., Y.K. and G.X. were employed by Shanghai Pharmaceuticals Holding Co., Ltd. at the time this work was done.
(© 2022 American Chemical Society.)