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 inh...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(2 H)-ones were designed as inhibitors of aldosterone synthase.Six compounds(5 j,5 l,5 m 5 w,5 x and 5 y)distinguished themselves with potent inhibition(IC50<100 nmol/L)and high selectivity over homogenous 11β-hydroxylase.As the most promising compound,5 x exhibited an IC_(50) of 12 nmol/L and an excellent selectivity factor(SF)of157,which are both superior to those of the re ference fadrazole(IC_(50)=21 nmol/L,SF=7).Importantly,5 x showed no inhibition against steroidogenic CYP17,CYP19 and a panel of hepatic CYP enzymes indicating an outstanding sa fety profile.As it manifested satis factory pharmacokinetic pro perties in rats,compound5 x was considered as a drug candidate for further development.展开更多
Primary aldosteronism(PA)is the most common form of secondary hypertension,with its main manifestations including hypertension and hypokalemia.Early identification of PA is extremely important as PA patients can easil...Primary aldosteronism(PA)is the most common form of secondary hypertension,with its main manifestations including hypertension and hypokalemia.Early identification of PA is extremely important as PA patients can easily develop cardiovascular complications such as atrial fibrillation,stroke,and myocardial infarction.The past decade has witnessed the rapid advances in the genetics of PA,which has shed new light on PA treatment.While surgery is the first choice for unilateral diseases,bilateral lesions can be treated with mineralocorticoid receptor antagonists(MRAs).The next-generation non-steroidal MRAs are under investigations.New medications including calcium channel blockers,macrophage antibiotics,and aldosterone synthase inhibitors have provided a new perspective for the medical treatment of PA.展开更多
基金supported by the National Natural Science Foundation of China(No.81872739)the Zhujiang Distinguish Professorship of Guangdong Province,China(2018)+1 种基金the International Scientific Collaboration Program of Guangdong Province,China(No.2020A0505100053)the Key Research and Development Program of Guangdong Province,China(No.2019B02021002)。
文摘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(2 H)-ones were designed as inhibitors of aldosterone synthase.Six compounds(5 j,5 l,5 m 5 w,5 x and 5 y)distinguished themselves with potent inhibition(IC50<100 nmol/L)and high selectivity over homogenous 11β-hydroxylase.As the most promising compound,5 x exhibited an IC_(50) of 12 nmol/L and an excellent selectivity factor(SF)of157,which are both superior to those of the re ference fadrazole(IC_(50)=21 nmol/L,SF=7).Importantly,5 x showed no inhibition against steroidogenic CYP17,CYP19 and a panel of hepatic CYP enzymes indicating an outstanding sa fety profile.As it manifested satis factory pharmacokinetic pro perties in rats,compound5 x was considered as a drug candidate for further development.
基金Supported by the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2019XK320027).
文摘Primary aldosteronism(PA)is the most common form of secondary hypertension,with its main manifestations including hypertension and hypokalemia.Early identification of PA is extremely important as PA patients can easily develop cardiovascular complications such as atrial fibrillation,stroke,and myocardial infarction.The past decade has witnessed the rapid advances in the genetics of PA,which has shed new light on PA treatment.While surgery is the first choice for unilateral diseases,bilateral lesions can be treated with mineralocorticoid receptor antagonists(MRAs).The next-generation non-steroidal MRAs are under investigations.New medications including calcium channel blockers,macrophage antibiotics,and aldosterone synthase inhibitors have provided a new perspective for the medical treatment of PA.
