title: Pharmacological properties of YM-26365, a low molecular weight, orally active renin inhibitor.
abstract: 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.
authors.affiliation: Cardiovascular and Atherosclerosis Research Laboratories, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Shibasaki
authors.forename: K
authors.initials: K
authors.lastname: Shibasaki
authors.forename: M
authors.initials: M
authors.lastname: Ichihara
authors.forename: O
authors.initials: O
authors.lastname: Inagaki
authors.forename: I
authors.initials: I
authors.lastname: Yanagisawa
authors.forename: T
authors.initials: T
authors.lastname: Takenaka
authors.forename: K
authors.initials: K
authors.lastname: Murakami
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001570:Benzodiazepinones / Q000493:pharmacokinetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D008970:Molecular Weight; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D000092502:Renin Inhibitors
chemical_list: D001570:Benzodiazepinones; D000092502:Renin Inhibitors; C092925:YM 26365