Discovery of benzimidazole derivatives as orally active renin inhibitors: Optimization of 3,5-disubstituted piperidine to improve pharmacokinetic profile.

Autor: Tokuhara H; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan; Axcelead Drug Discovery Partners, Inc., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-0012, Japan., Imaeda Y; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan., Fukase Y; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan., Iwanaga K; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan., Taya N; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan; Axcelead Drug Discovery Partners, Inc., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-0012, Japan., Watanabe K; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan., Kanagawa R; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan; PRA Health Sciences KK, 3-8, Doshomachi 2-chome, Chuo-ku, Osaka 541-0045, Japan., Matsuda K; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan; SCOHIA PHARMA Inc., 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan., Kajimoto Y; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan; SPERA PHARMA,1nc., 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-0024, Japan., Kusumoto K; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan., Kondo M; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan; Axcelead Drug Discovery Partners, Inc., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-0012, Japan., Snell G; Takeda California, Inc, 10410 Science Center Drive, San Diego, CA 92121, United States., Behnke CA; Takeda California, Inc, 10410 Science Center Drive, San Diego, CA 92121, United States; 10996 Torreyana Rd. Suite 280, San Diego, CA 92121, United States., Kuroita T; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: takanobu.kuroita@takeda.com.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2018 Jul 23; Vol. 26 (12), pp. 3261-3286. Date of Electronic Publication: 2018 Apr 27.
DOI: 10.1016/j.bmc.2018.04.051
Abstrakt: We previously identified 2-tert-butyl-4-[(3-methoxypropyl)amino]-N-(2-methylpropyl)-N-[(3S,5R)-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.
(Copyright © 2018 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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