Renin inhibitors. Synthesis of transition-state analogue inhibitors containing phosphorus acid derivatives at the scissile bond.

摘要: The synthesis of five amino phosphorus derivatives, 1a-e, is described. derivatives were incorporated into a series (18) analogues the 5-14 portion angiotensinogen, in most cases at scissile Leu-Val bond. resultant compounds tested vitro for their ability to inhibit human plasma renin. Replacement bond with phosphinic analogue Leu10-Val11 (1b) gave potent inhibitors, having IC50 = 7.5 x 10(-8) M H-Pro-His-Pro-Phe-His-(1b)-Ile-His-Lys-OH and 1.0 10(-7) Z-Arg-Arg-Pro-Phe-His-(1b)-Ile-His-NH2. shorter phosphonic acid sequence Z-Pro-Phe-His-(1d) retained biological activity an 6.4 10(-6) M.