title: Discovery of TAK-272: A Novel, Potent, and Orally Active Renin Inhibitor.
abstract: The aspartic proteinase renin is an attractive target for the treatment of hypertension and cardiovascular/renal disease such as chronic kidney disease and heart failure. We introduced an S1' site binder into the lead compound1guided by structure-based drug design (SBDD), and further optimization of physicochemical properties led to the discovery of benzimidazole derivative10(1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-yl)carbonylpiperidin-3-yl]-1H-benzimidazole-2-carboxamide hydrochloride, TAK-272) as a highly potent and orally active renin inhibitor. Compound10demonstrated good oral bioavailability (BA) and long-lasting efficacy in rats. Compound10is currently in clinical trials.
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Yasuhiro
authors: Y
authors: Imaeda
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Hidekazu
authors: H
authors: Tokuhara
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Yoshiyuki
authors: Y
authors: Fukase
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Ray
authors: R
authors: Kanagawa
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Yumiko
authors: Y
authors: Kajimoto
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Keiji
authors: K
authors: Kusumoto
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Mitsuyo
authors: M
authors: Kondo
authors: Takeda California, Inc. , 10410 Science Center Drive, San Diego, California 92121, United States.
authors: Gyorgy
authors: G
authors: Snell
authors: Takeda California, Inc. , 10410 Science Center Drive, San Diego, California 92121, United States.
authors: Craig A
authors: CA
authors: Behnke
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Takanobu
authors: T
authors: Kuroita
keywords: Renin inhibitor; SBDD; TAK-272; benzimidazole; dTg rat; hypertension