Pharmacological properties of YM-26365, a low molecular weight, orally active renin inhibitor

This report describes the pharmacological properties of a novel renin inhibitor (YM-26365: (3R)-3-[3-[(1S)-1-cyclohexylmethyl-2-hydroxy-3- [(1-methyl-5-tetrazolyl)thio]propyl]ureido]-1-methyl-5-phenyl- 2,3-dihydro-1H-1,4-benzodiazepin-2-one) with molecular weight 577 and no peptide bonds. YM-26365 inhibited human plasma renin with an IC50 value of 2.9 x 10(-6) M, but did not affect plasma renin from dogs, rabbits, and rats at 10(-4) M. YM-26365 inhibited not only human renin, but also cathepsin D with an IC50 value of 1.7 x 10(-5) M. This compound competitively inhibited the reaction between recombinant human renin and N-acetyl tetradecapeptide with a Ki value of 1.1 x 10(-6) M. In pithed spontaneously hypertensive rats, YM-26365 at 10 mg/kg i.v. significantly antagonized the pressor response to recombinant human renin, but did not affect responses to angiotensin II, angiotensin I, norepinephrine, or arginine vasopressin. Similarly, oral administration of YM-26365 (10 and 30 mg/kg) to pithed spontaneously hypertensive rats caused a shift to the right of the recombinant human renin dose-pressor response curve. Systemic bioavailability as determined on the basis of the ratio of the total area under the plasma concentration-time curve after 3 mg/kg i.v. and 30 mg/kg orally to rats was 9.6%. These results demonstrate that YM-26365 is a weak but orally absorbed, low molecular weight renin inhibitor.