Pharmacological Properties of YM-21095, A Potent and Highly Specific Renin Inhibitor

: A novel renin inhibitor, YM-21095 [2RS), (3S)-3-[N alpha-[1,4-dioxo-4-morpholino-2-(1-naphthylmethyl)-buthyl]-L- histidil-amino]-4-cyclohexyl-1-[(1-methyl-5-tetrazolyl)thio]-2-but anol), has been synthesized in our laboratories. The aim of this study was to evaluate the pharmacological properties of YM-21095 in in vitro and in vivo experiments. YM-21095 inhibited human renin with an IC50 value of 4.7 x 10(-10) mol/L. YM-21095 was also a potent inhibitor against squirrel monkey renin, but less effective against renins from dog, rabbit, and rat. The effect of YM-21095 is highly specific for renin, since it did not inhibit cathepsin D, pepsin, or angiotensin converting enzyme up to a concentration of 10(-4) mol/L. YM-21095 was resistant to proteolytic actions of the enzymes (pepsin, chymotrypsin, trypsin) and squirrel monkey tissue homogenates (liver, kidney, small intestine). Intravenous infusion of YM-21095 (0.1 to 100 micrograms/kg/min) decreased mean blood pressure and inhibited plasma renin activity in a dose-dependent manner with no effect on heart rate in anesthetized sodium-depleted and sodium-replete squirrel monkeys. The hypotensive effect of YM-21095 in sodium-depleted squirrel monkeys was about ten times as potent as that in sodium-replete squirrel monkeys. Oral administration of YM-21095 to conscious sodium-depleted squirrel monkeys produced dose-related decreases of systolic blood pressure. We conclude that YM-21095 is a potent and highly specific inhibitor of primate renin and produces a blood pressure lowering effect.