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

M C MC Allen, W W Fuhrer, B B Tuck, R R Wade, and J M JM Wood

J Med Chem 32(7):1652-61 (1989) PMID 2661820

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

DOI: 10.1021/jm00127a041
Version: za2963e q8za7 q8zb8 q8zcd q8zd9 q8ze5 q8zf8 q8zg4

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