Imaeda Yasuhiro, Tokuhara Hidekazu, Fukase Yoshiyuki, Kanagawa Ray, Kajimoto Yumiko, Kusumoto Keiji, Kondo Mitsuyo, Snell Gyorgy, Behnke Craig A, Kuroita Takanobu
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Takeda California, Inc. , 10410 Science Center Drive, San Diego, California 92121, United States.
ACS Med Chem Lett. 2016 Sep 12;7(10):933-938. doi: 10.1021/acsmedchemlett.6b00251. eCollection 2016 Oct 13.
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 compound guided by structure-based drug design (SBDD), and further optimization of physicochemical properties led to the discovery of benzimidazole derivative (1-(4-methoxybutyl)--(2-methylpropyl)--[(3,5)-5-(morpholin-4-yl)carbonylpiperidin-3-yl]-1benzimidazole-2-carboxamide hydrochloride, TAK-272) as a highly potent and orally active renin inhibitor. Compound demonstrated good oral bioavailability (BA) and long-lasting efficacy in rats. Compound is currently in clinical trials.
天冬氨酸蛋白酶肾素是治疗高血压和心血管/肾脏疾病（如慢性肾病和心力衰竭）的一个有吸引力的靶点。我们在基于结构的药物设计（SBDD）指导下，将一个S1'位点结合剂引入先导化合物，进一步优化物理化学性质后发现了苯并咪唑衍生物（1-(4-甲氧基丁基)-2-(2-甲基丙基)-5-[(3,5)-5-(吗啉-4-基)羰基哌啶-3-基]-1H-苯并咪唑-2-甲酰胺盐酸盐，TAK-272），它是一种高效且口服活性的肾素抑制剂。该化合物在大鼠中表现出良好的口服生物利用度（BA）和持久疗效。该化合物目前正在进行临床试验。
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