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

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.