Biochemical and Biophysical Research Communications
A novel nonpeptidic, orally active renin inhibitor
Abstract
BW-175 is a newly synthesized renin inhibitor which is a nonpeptidic, norleucine analog. Its IC50 values for renin activity in human, squirrel monkey, marmoset, dog, hog, rabbit and rat plasma were 3.3, 6.6, 2.4, 42, 110, 86 and 3500 nM, respectively, and 26 μ M for cathepsin D. Pepsin and angiotensin converting enzyme were hardly inhibited at 10−4 M. BW-175 showed an oral bioavailability of 2.8% at 10 mg/kg and 9.7% at 30 mg/kg in rats. In normotensive, furosemide-treated high-renin marmosets, BW-175(30 mg/kg p.o.) caused an intensive reduction in plasma renin activity and plasma angiotensin I formation, associated with a reduction in systolic blood pressure of 10–20 mm Hg for 2 hours.
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Cited by (33)
A facile synthesis of (2S,3R,4S)-4-amino-5-cyclohexyl-1-morpholino-2,3-pentanediol, the C-terminal compound of renin inhibitor BW-175
1995, TetrahedronA facile synthesis of (2S, 3R, 4S)-4-amino-5-cyclohexyl-1-morpholino-2, pentanediol (ACMP), the C-terminal compounds of renin inhibitor BW-175 is described.
Renin Inhibitors
1995, Progress in Medicinal ChemistryThis chapter focuses on renin inhibitors. Renin is the first and rate-limiting enzyme in the renin angiotensin system (RAS). It is a 3740 Kd glycoprotein that is secreted primarily by the juxtaglomerular cells in the kidney in response to decreased perfusion pressure or a fall in plasma sodium concentration. Renin is released as either inactive prorenin or as the fully active enzyme. Although prorenin is the major form of circulating renin, the site at which it is converted into active renin by removal of the N-terminal43-amino acid prosegment has not been resolved. An enzyme believed to be the correct processing enzyme has been identified in the human kidney; however, enzymes capable of activating prorenin have also been found in vascular endothelial cells and in human neutrophils. Isoelectric focusing has shown that active renin exists as at least seven isoforms. Human renin has been cloned and expressed, permitting the determination of crystal structures for both the glycosylated and nonglycosylated enzyme. Renin belongs to the aspartic proteinase family of proteolytic enzymes, other members of which include the mammalian enzymes pepsin, cathepsin D, cathepsin E, gastricsin, and chymosin, the fungal proteinases penicillopepsin, endothiapepsin, and rhizopuspepsin, as well as plant and retroviral proteinases. Several methods have been employed to evaluate the in vitro potency of renin inhibitors. All share the common feature that they determine the ability of a test compound to block the renin-mediated conversion of a substrate to angiotensin I, which is generally quantified by radioimmunoassay.
Role of intestinal transport and first pass liver extraction on oral delivery of renin inhibitor compounds
1994, International Journal of PharmaceuticsThe absolute bioavailabilities of three renin inhibitor compounds, one uncharged (compound I) and two positively charged (compounds II and III), were found to be comparable (1—3%). To determine the role of intestinal transport and first pass liver extraction (FPLE) in the oral delivery of these compounds intravenous, intraportal, intraduodenal and intraperitoneal studies were performed in the rat. In the intraduodenal studies, drug solutions were injected into the duodenum of anesthetized rats and portal and systemic blood was collected. In the intraportal studies, the drug solutions were injected into the portal vein and systemic blood was collected. From the ratio of the area under the drug concentration-time curves (tAUC) for the oral and intraportal studies, the extent of intestinal transport of compounds I–III was estimated as 9.7, 2.2 and 2.2%, respectively. In the intraduodenal studies the maximum portal plasma concentrations of compounds I–III were 2.8, 0.5 and 0.2 μg/ml, respectively. The tAUC of compound I in portal plasma was 8–26-times higher than those for compounds II and III. From comparison of the intraportal and intravenous tAUC values, the FPLE of compounds I–III was estimated as 76 ± 4, 61 ± 3 and 8 ± 23% (mean ± SE), respectively. Overall, the results indicated that the intestinal transport and FPLE of compound I was the highest among the three analogs. Compound II showed low intestinal transport and high FPLE and compound III showed low intestinal transport and low but variable FPLE.
KRI-1314: An Orally Effective Inhibitor of Human Renin
1993, The Japanese Journal of PharmacologyBiochemical 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 Leul0-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 × 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.
Absolute oral bioavailability of ditekiren, a renin inhibitor peptide, in conscius rats
1991, International Journal of PharmaceuticsAbsolute oral bioavailability of ditekrine, a renin inhibitor peptide, was determined in rats. Unanesthetized rats which had been fitted with chronic biliary and superior vena cava cannulae were dosed either orally (p.o.) at 50 mg/kg or intravenously (i.v.) at 10 mg/kg with ditekiren. Serum ditekiren levels were measured with an activity assay and biliary ditekiren was quantitated by both activity assay and HPLC assay. Cumulative biliary elimination (BT) indicated that oral bioavailability was 1.3%. The disposition kinetics of ditekiren were independent of route of administration. These data indicate that ditekiren is poorly absorbed across the gut and that, once in the systemic circulation, ditekiren is rapidly cleared. Even though oral bioavailability was low, serum ditekiren levels were equivalent to 4–8 times the in vitro IC50 for renin inhibition for this peptide throughout the 2.5 h after oral administration that blood levels were monitored.
Renin Inhibitors
1991, Advances in PharmacologyThis chapter reviews the advances and challenges encountered in the process of discovering and developing renin inhibitors. Renin inhibitors have emerged as agents capable of reducing blood pressure in man and experimental animals when administered intravenously. These compounds are more specific than angiotensin-converting enzyme (ACE) inhibitors, but they exert their actions through vasodilation—for example, peripheral, renal. The earlier renin inhibitors are high-molecular-weight peptides. However, structural modification and physicochemical optimization have led to smaller dipeptide inhibitors, which represent the most promising leads for drug candidacy to date. The dipeptide-renin inhibitors lack good oral bioavailability caused by either limited gastrointestinal absorption or high hepatic extraction, or both. These insufficiencies provide the challenge for the improvement of the dipeptide-renin inhibitors series and the development of nonpeptide-rennin inhibitors. Thus, the evolution of renin inhibitors continues. If solutions to poor gastrointestinal absorption and rapid hepatic extraction are found, then rennin inhibitors play a significant role in the treatment and control of hypertension and renin-angiotensin-aldosterone system (RAAS)-related diseases.