Citation: Haichao Zhu, Meihua Liu, Haiyan Li, Ting Guan, Qi Zhang, Yang Chen, Yingxiang Liu, Rolf R. Hartmann, Lina Yin, Qingzhong Hu. Design, synthesis and biological evaluation of pyridyl substituted benzoxazepinones as potent and selective inhibitors of aldosterone synthase[J]. Chinese Chemical Letters, ;2021, 32(7): 2327-2332. doi: 10.1016/j.cclet.2020.11.021 shu

Design, synthesis and biological evaluation of pyridyl substituted benzoxazepinones as potent and selective inhibitors of aldosterone synthase

Haichao Zhu ^{a, 1} ,
Meihua Liu ^{a, 1} ,
Haiyan Li ^a ,
Ting Guan ^a ,
Qi Zhang ^a ,
Yang Chen ^a ,
Yingxiang Liu ^a ,
Rolf R. Hartmann ^b ,
Lina Yin ^{a, *,} ,
Qingzhong Hu ^{a, *,}

a.
School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 51006, China
b.
Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, D-66123, Saarbrücken, Germany

linayin@gzucm.edu.cn

huqqzh@gzucm.edu.cn

Received Date: 30 August 2020
Revised Date: 2 October 2020
Accepted Date: 10 November 2020
Available Online: 10 November 2020

Figures(3)

Exorbitant aldosterone is closely associated with various severe diseases, including congestive heart failure and chronic kidney disease. As aldosterone synthase is the pivotal enzyme in aldosterone biosynthesis, its inhibition constitutes a promising treatment for these diseases. Via a structure-based approach, a series of pyridyl substituted 3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-ones were designed as inhibitors of aldosterone synthase. Six compounds (5j, 5l, 5m 5w, 5x and 5y) distinguished themselves with potent inhibition (IC₅₀ < 100 nmol/L) and high selectivity over homogenous 11β-hydroxylase. As the most promising compound, 5x exhibited an IC₅₀ of 12 nmol/L and an excellent selectivity factor (SF) of 157, which are both superior to those of the reference fadrazole (IC₅₀=21 nmol/L, SF=7). Importantly, 5x showed no inhibition against steroidogenic CYP17, CYP19 and a panel of hepatic CYP enzymes indicating an outstanding safety profile. As it manifested satisfactory pharmacokinetic properties in rats, compound 5x was considered as a drug candidate for further development.
- Aldosterone synthase,
- Selective inhibitors,
- Benzoxazepinones,
- Heart failure,
- Renal diseases
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