Structure-based design of a new series of N-(piperidin-3-yl)pyrimidine-5-carboxamides as renin inhibitors

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• 作者：Yasuhiro Imaeda^a ; ^{yasuhiro.imaeda@takeda.com" class="auth_mail" title="E-mail the corresponding author} ; Michiko Tawada^a ; Shinkichi Suzuki^a ; Masaki Tomimoto^a ; Mitsuyo Kondo^a ; Naoki Tarui^a ; Tsukasa Sanada^a ; Ray Kanagawa^a ; Gyorgy Snell^b ; Craig A. Behnke^b ; ^&dagger ; ; Keiji Kubo^a ; Takanobu Kuroita^a
• 关键词：AcOH ; acetic acid ; Ang I ; angiotensin I ; Ang II ; angiotensin II ; AUC ; area under the blood concentration&ndash ; time curve ; C5min ; concentration in plasma 5  ; min after administration ; CLtotal ; total clearance ; Cmax ; maximum concentration in plasma ; DIEA ; N ; N-diisopropylethylamine ; Et3N ; triethylamine ; EtOAc ; ethyl acetate ; EtOH ; ethanol ; F ; rat bioavailability ; HAC ; heavy atom count ; HOBt ; 1-hydroxybenzotriazole hydrate ; hPRA ; human plasma renin activity ; i-PrOH ; isopropanol ; LE ; ligand effic
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 November 2016
• 年：2016
• 卷：24
• 期：22
• 页码：5771-5780
• 全文大小：1549 K

文摘

The action of the aspartyl protease renin is the rate-limiting initial step of the renin-angiotensin-aldosterone system. Therefore, renin is a particularly promising target for blood pressure as well as onset and progression of cardiovascular and renal diseases. New pyrimidine derivatives 5–14 were designed in an attempt to enhance the renin inhibitory activity of compound 3 identified by our previous fragment-based drug design approach. Introduction of a basic amine essential for interaction with the two aspartic acids in the catalytic site and optimization of the S1/S3 binding elements including an induced-fit structural change of Leu114 (‘Leu-in’ to ‘Leu-out’) by a rational structure-based drug design approach led to the discovery of N-(piperidin-3-yl)pyrimidine-5-carboxamide 14, a 65,000-fold more potent renin inhibitor than compound 3. Surprisingly, this remarkable enhancement in the inhibitory activity of compound 14 has been achieved by the overall addition of only seven heavy atoms to compound 3. Compound 14 demonstrated excellent selectivity over other aspartyl proteases and moderate oral bioavailability in rats.