With the aim of finding new renin inhibitors with improved bioavailability properties, two angiotensinogen transition state analogues 1a and 1b, containing a novel unnatural amino acid at the P(2) position, namely the (2R,3S)- and (2S,3S)-2-amino-3-(1,3-dithiolan-2-yl)-3-hydroxypropanoic acid (ADHPA), have been synthesized and tested for human renin inhibitory activity and for chemical and enzymatic stability. Only compound 1a (the S-isomer) possessed a significant activity, which was lower than that of the corresponding histidyl derivative KRI-1314, and combined with a low stability to the gut enzyme chymotrypsin.

01 Jan 1994·Folia Pharmacologica Japonica

Hypotensive action of human renin inhibitor KRI-1314 in the common marmoset.

Article

Author: Kubota, Tetsuhiro ; Etoh, Yasuo ; Murakami, Makoto ; Saitoh, Hiroshi ; Miyazaki, Mizuo

The possibility of using KRI-1314, a new cyclohexylnorstatine derivative, as an antihypertensive drug was examined using common marmosets. KRI-1314 strongly inhibited plasma renin activity (PRA) in both humans and marmosets, with a 50% inhibitory concentration of 4.7 x 10(-9) and 6.9 x 10(-9) M, respectively. In anesthetized marmosets, the increase in both blood pressure and PRA induced by bolus intravenous injection of RH-renin (0.15 microgram/kg) was suppressed by constant intravenous infusion of KRI-1314 (0.01 and 0.1 mg/kg/min) in a dose-dependent manner. In the sustained hypertension induced by continuous intravenous infusion of RH-renin (0.1 microgram/kg/min), a dose-dependent hypotensive response was produced by bolus intravenous injection of KRI-1314 (0.03-3 mg/kg). In the sodium-depleted model, whose PRA was increased by a two-week low-sodium diet coupled with furosemide loading, both intravenous injection (0.1-3 mg/kg) and oral administration (10 and 30 mg/kg) of KRI-1314 to anesthetized and conscious animals, respectively, lowered blood pressure dose-dependently with PRA suppression. The hypotensive activity of orally administered KRI-1314 (30 mg/kg) was almost equal to that of orally administered captopril (1 mg/kg). KRI-1314 did not affect heart rate in any of the experiments. These results indicate that the potent human renin inhibitor KRI-1314 may become an orally effective drug for treating renin-dependent hypertension.

01 Jan 1993·Japanese Journal of Pharmacology

KRI-1314: An Orally Effective Inhibitor of Human Renin

Article

Author: Yasuo Etoh ; Hiroshi Saitoh ; Noboru Toda ; Mizuo Miyazaki

Biochemical and pharmacological properties of KRI-1314, a newly synthesized, low molecular weight (M.W.: 690) renin inhibitor, were investigated in vitro and in vivo. The novel amino acid norstatine, which is shorter in chain length than the well-known statine, was incorporated into KRI-1314 as a tetrahedral transition-state analogue for the Leu10-Val11 scissile peptide in the renin substrate. KRI-1314 more strongly inhibited plasma renins from primates than those from dogs, rabbits, guinea pigs and rats. KRI-1314 competitively inhibited highly-purified human renin with a Ki value of 9.9 x 10(-10) M. KRI-1314 strongly inhibited the tissue renin-like activities of various organs from Japanese monkeys, with IC50 values on the order of 10(-8) M. KRI-1314 was also very stable in various tissue homogenates from Japanese monkeys. Both intravenous (from 0.25 to 3 mg/kg) and oral (10 and 30 mg/kg) administration of KRI-1314 to anesthetized and conscious sodium-depleted Japanese monkeys, respectively, significantly lowered the blood pressure and plasma renin activity without affecting the heart rate. In Japanese monkeys, KRI-1314 was continuously detected in the plasma up to at least 7 hr after oral administration of 10 and 30 mg/kg. These results demonstrate that KRI-1314 is a highly potent, primate-selective and long-lasting oral renin inhibitor with a blood pressure lowering effect.

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Indication	Highest Phase	Country/Location	Organization	Date
Hypertension	Discovery	JP	Kissei Pharmaceutical Co., Ltd.	-

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