Structure-based design of a new series of N-(piperidin-3-yl)pyrimidine-5-carboxamides as renin inhibitors. Issue 22 (15th November 2016)

• Record Type: Journal Article
• Authors: Imaeda, Yasuhiro; Tawada, Michiko; Suzuki, Shinkichi; Tomimoto, Masaki; Kondo, Mitsuyo; Tarui, Naoki; Sanada, Tsukasa; Kanagawa, Ray; Snell, Gyorgy; Behnke, Craig A.; Kubo, Keiji; Kuroita, Takanobu
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 22(2016)
• Page Start: 5771
• Page End: 5780
• Publication Date: 2016-11-15
• Subjects: AcOH acetic acid -- Ang I angiotensin I -- Ang II angiotensin II -- AUC area under the blood concentration–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 efficiency -- MeOH methanol -- MRT mean residence time -- Pd/C palladium on carbon -- RAAS renin-angiotensin-aldosterone system -- Rt retention time -- Vd(ss) volume of distribution at steady state -- WSC (1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide; Renin inhibitor -- Structure-based drug design (SBDD) -- Crystal structure -- N-(Piperidin-3-yl)pyrimidine-5-carboxamide; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.09.030
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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 derivatives5 –14 were designed in an attempt to enhance the renin inhibitory activity of compound3 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-carboxamide14, a 65, 000-fold more potent renin inhibitor than compound3 . Surprisingly, this remarkable enhancement in the inhibitory activity of compound14 has been achieved by the overall addition of only seven heavy atoms to compound3 . Compound14 demonstrated excellent selectivity over other aspartyl proteases and moderate oral bioavailability in rats.