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Lead optimization of 5-amino-6-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)-4-hydroxyhexanamides to reduce a cardiac safety issue: Discovery of DS-8108b, an orally active renin inhibitor

2013; Elsevier BV; Volume: 21; Issue: 11 Linguagem: Inglês

10.1016/j.bmc.2013.03.022

1464-3391

Yuji Nakamura, Teppei Fujimoto, Yasuyuki Ogawa, Hidenori Namiki, Sayaka Suzuki, Masayoshi Asano, Chie Sugita, Akiyoshi Mochizuki, Shojiro Miyazaki, Kazuhiko Tamaki, Yoko Nagai, Shinichi Inoue, Takahiro Nagayama, Mikio Kato, Katsuyoshi Chiba, Kiyoshi Takasuna, Takahide Nishi,

Nitric Oxide and Endothelin Effects

With the aim to address an undesired cardiac issue observed with our related compound in the recently disclosed novel series of renin inhibitors, further chemical modifications of this series were performed. Extensive structure-activity relationships studies as well as in vivo cardiac studies using the electrophysiology rat model led to the discovery of clinical candidate trans-adamantan-1-ol analogue 56 (DS-8108b) as a potent renin inhibitor with reduced potential cardiac risk. Oral administration of single doses of 3 and 10 mg/kg of 56 in cynomolgus monkeys pre-treated with furosemide led to significant reduction of mean arterial blood pressure for more than 12 h.