Synthesis and optimization of novel (3S,5R)-5-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)piperidine-3-carboxamides as orally active renin inhibitors
| Autor: | Shojiro Miyazaki, Kazuhiko Tamaki, Chie Sugita, Yoko Nagai, Teppei Fujimoto, Akiyoshi Mochizuki, Yuji Nakamura, Takahiro Nagayama, Shin-ichi Inoue, Katsuyoshi Chiba, Yutaka Mori, Ogawa Yasuyuki, Takahide Nishi |
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| Rok vydání: | 2013 |
| Předmět: |
medicine.medical_specialty
Clinical Biochemistry hERG Pharmaceutical Science High renin Administration Oral Blood Pressure Pharmacology Biochemistry Piperazines chemistry.chemical_compound Structure-Activity Relationship Piperidines Oral administration Furosemide Internal medicine Drug Discovery Renin–angiotensin system Renin medicine Animals Protease Inhibitors Molecular Biology biology Chemistry Organic Chemistry Chemical modification Amides Rats Disease Models Animal Macaca fascicularis Endocrinology Orally active Hypertension biology.protein Molecular Medicine Piperidine Rats Transgenic medicine.drug Half-Life |
| Zdroj: | Bioorganicmedicinal chemistry. 21(18) |
| ISSN: | 1464-3391 |
| Popis: | We report synthesis and optimization of a series of (3 S ,5 R )-5-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)piperidine-3-carboxamides as renin inhibitors. Chemical modification of P 1 ′ P 1 ′ , P 2 ′ P 2 ′ and P 3 portions led to a promising 3,5-disubstituted piperidine 32o showing high renin inhibitory activity and favorable oral exposure in both rats and cynomolgus monkeys with acceptable CYP and hERG current inhibition. Compound 32o exhibited a significant blood pressure lowering effect by oral administration in two hypertensive animal models, double transgenic rats and furosemide pretreated cynomolgus monkeys. |
| Databáze: | OpenAIRE |
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