Disease relevance of RS-5139

• METHODS: In dogs with myocardial ischemia, we infused an ACE inhibitor (temocaprilat, 10 microg/kg/min) or ARB (RNH-6270, 10 microg/kg/min) into the coronary artery [1].
• DNA fragmentation, Lactate dehydrogenase (LDH) release, and caspase-3 activity were measured in cultured HAEC after exposure to hypoxia in the presence or absence of an AT1-RA (candesartan, CS) and/or an ACEI (temocaprilat, TC) [2].
• Pravastatin, temocaprilat, CV-11974 or a nitric oxide synthase inhibitor, L-NAME was administered from 60 min prior to the global ischemia [3].

High impact information on RS-5139

• The uptake of temocaprilat into isolated rat hepatocytes exhibited saturation with a Km of 20.9 microM and a Vmax of 0.21 nmol/min/mg protein [4].
• Transport of temocaprilat into rat hepatocytes: role of organic anion transporting polypeptide [4].
• These data suggest that temocaprilat is effectively excreted in bile via cMOAT that is deficient in EHBR and that many of other ACE inhibitors have low affinity for cMOAT [5].
• The initial uptake rate of ATP-dependent transport of temocaprilat showed saturation kinetics; we obtained an apparent V(max) value of 1.14 nmol/min/mg protein and a K(m) value 92.5 microM [5].
• Temocapril was almost completely hydrolyzed to temocaprilat during transport across Caco-2 cells [6].

Chemical compound and disease context of RS-5139

• In conclusion, the combination of temocaprilat and CV-11974 showed significant potential for improving myocardial energy metabolism and relaxation during both myocardial ischemia and reperfusion [7].
• TAK-044 and/or temocaprilat was administered from 40 min prior to the global ischemia [8].
• The effect of an endothelin (ET) A/ETB receptor antagonist, TAK-044, and/or an angiotensin converting enzyme (ACE) inhibitor, temocaprilat, on myocardial metabolism and contraction during ischemia and reperfusion was examined by phosphorus 31-nuclear magnetic resonance (31P-NMR) in Langendorff rabbit hearts [8].

Biological context of RS-5139

• Single dose and steady state pharmacokinetics of temocapril and temocaprilat in young and elderly hypertensive patients [9].
• Statistically significant differences were detected in AUC and AUCss for temocaprilat as well as in CL(R) for temocapril and temocaprilat, respectively, after a single dose and at steady state [9].

Anatomical context of RS-5139

• Temocaprilat at 1 micromol/l inhibited high glucose-induced membrane-bound protein kinase C activity in human aortic endothelial cells [10].
• In L6 skeletal muscle cells, 2-DG uptake was increased by temocaprilat, and Hoe140 inhibited this effect of temocaprilat but not that of insulin [11].

Associations of RS-5139 with other chemical compounds

• Temocaprilat, a novel angiotensin-converting enzyme inhibitor, is excreted in bile via an ATP-dependent active transporter (cMOAT) that is deficient in Eisai hyperbilirubinemic mutant rats (EHBR) [5].
• CONCLUSIONS: These results indicate that impaired renal function has only a limited effect on the pharmacokinetics of temocapril and its active metabolite, temocaprilat [12].
• Twenty-one hearts were divided into three experimental groups consisting of 7 hearts each: a Tem+CV group perfused with a combination of temocaprilat and CV-11974; a Tem+CV+L-NAME group perfused with a combination of temocaprilat and CV-11974 plus L-NAME, and a control group [7].
• The dose-dependent inhibition of the up-take of [3H]-estradiol-17beta-D-glucuronide and [3H]-2,4-dinitrophenyl-S-glutathione, which are good substrates for cMOAT, in canalicular membrane vesicles (CMVs) prepared from Sprague-Dawley rats was determined in the presence of trandolaprilat and temocaprilat [13].

Gene context of RS-5139

• The Mrp2 protein expression in dog liver was only 10% of that in rat liver and was comparable with the reported difference in the biliary excretion clearance of temocaprilat as Mrp2 substrate [14].
• The N-succinimmidyl ester of RS-5139 was coupled with bovine serum albumin (BSA) and its conjugate was used as an immunogen [15].
• The effect of angiotensin converting enzyme (ACE) inhibitor, temocaprilat and/or angiotensin II type 1 (AT1) receptor antagonist, CV-11974 on myocardial metabolism and contraction during ischemia and reperfusion was examined by phosphorus 31-nuclear magnetic resonance (31P-NMR) in Langendorff rabbit hearts [16].

Analytical, diagnostic and therapeutic context of RS-5139

• Enzyme immunoassay of the active metabolite (RS-5139) of angiotensin converting enzyme inhibitor (CS-622) [15].

References