Discovery of benzimidazole derivatives as orally active renin inhibitors: Optimization of 3, 5-disubstituted piperidine to improve pharmacokinetic profile. Issue 12 (23rd July 2018)

• Record Type: Journal Article
• Authors: Tokuhara, Hidekazu; Imaeda, Yasuhiro; Fukase, Yoshiyuki; Iwanaga, Koichi; Taya, Naohiro; Watanabe, Koji; Kanagawa, Ray; Matsuda, Keisuke; Kajimoto, Yumiko; Kusumoto, Keiji; Kondo, Mitsuyo; Snell, Gyorgy; Behnke, Craig A.; Kuroita, Takanobu
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 12(2018)
• Page Start: 3261
• Page End: 3286
• Publication Date: 2018-07-23
• Subjects: BA bioavailability -- RAAS renin-angiotensin-aldosterone system -- BP blood pressure -- Ang I angiotensin I -- ACE Angiotensin-converting enzyme -- Ang II angiotensin II -- AT1 Ang II type I receptor -- DRI direct renin inhibitor -- TPSA topological polar surface area -- TCFH N, N, N′, N′-tetramethylchloroformamidinium hexafluorophosphate -- DIEA N, N-diisopropylethylamine -- DMF-DMA N, N-dimethylformamide dimethyl acetal -- rh-renin recombinant human renin -- hPRA human plasma renin activity -- HSA human serum albumin -- DCE 1, 2-dichloroethane -- ELISA enzyme-linked immunosorbent assay; Renin inhibitor -- Crystal structure -- Bioavailability -- Piperidine -- Topological polar surface area; 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.2018.04.051
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: We previously identified 2- tert -butyl-4-[(3-methoxypropyl)amino]- N -(2-methylpropyl)- N -[(3 S, 5 R )-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]pyrimidine-5-carboxamide 3 as a potent renin inhibitor. Since 3 showed unacceptably low bioavailability (BA) in rats, structural modification, using SBDD and focused on physicochemical properties was conducted to improve its PK profile while maintaining renin inhibitory activity. Conversion of the amino group attached at the 4-position of pyrimidine to methylene group improved PK profile and decreased renin inhibitory activity. New central cores with carbon side chains were explored to improve potency. We had designed a series of 5-membered azoles and fused heterocycles that interacted with the lipophilic S3 pocket. In the course of modification, renin inhibitory activity was enhanced by the formation of an additional hydrogen bonding with the hydroxyl group of Thr77. Consequently, a series of novel benzimidazole derivatives were discovered as potent and orally bioavailable renin inhibitors. Among those, compound 13 exhibited more than five-fold of plasma renin inhibition than aliskiren in cynomolgus monkeys at dose ratio.