Renin inhibitors. Synthesis of transition-state analogue inhibitors containing phosphorus acid derivatives at the scissile bond.
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.
Allen
M C
MC
Ciba-Geigy Pharmaceuticals Division, Horsham, West Sussex, England.
Fuhrer
W
W
Tuck
B
B
Wade
R
R
Wood
J M
JM
D000596:Amino Acids; D055598:Chemical Phenomena; D002621:Chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D006801:Humans; D010757:Phosphorous Acids; D012083:Renin / Q000097:blood; D013379:Substrate Specificity; D000092502:Renin Inhibitors
D000596:Amino Acids; D004791:Enzyme Inhibitors; D010757:Phosphorous Acids; D012083:Renin; D000092502:Renin Inhibitors