Pactimibe sulfate
(Synonyms: 帕替麦布,CS-505) 目录号 : GC61888
Pactimibe sulfate (CS-505) 是一种 ACAT1/2 双重抑制剂，对于 ACAT1 的 IC50 值为 4.9 µM，对于 ACAT2 的 IC50 值为 3.0 µM。Pactimibe sulfate (CS-505) 抑制 ACAT，其 IC50 值在肝细胞中是 2.0 µM，在巨噬细胞中是 2.7 µM，在 THP-1 细胞中是 4.7 µM。Pactimibe sulfate (CS-505) 非竞争性抑制 oleoyl-CoA，Ki 是5.6 µM。此外，Pactimibe sulfate (CS-505) 明显抑制胆固醇酯的形成，IC50 是6.7 µM。Pactimibe sulfate (CS-505) 具有抗动脉粥样硬化的潜力，可降低血浆胆固醇的活性。
Cas No.:608510-47-0
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Pactimibe sulfate (CS-505) is a dual ACAT1/2 inhibitor with IC50s of 4.9 µM and 3.0 µM, respectively. Pactimibe sulfate (CS-505) inhibits ACAT with IC50s of 2.0 µM, 2.7 µM, 4.7 µM in the liver, macrophages and THP-1 cells, respectively[1]. Pactimibe sulfate (CS-505) noncompetitively inhibits oleoyl-CoA with a Ki value of 5.6 µM. Moreover, Pactimibe sulfate (CS-505) obviously inhibits cholesteryl ester formation with an IC50 of 6.7 µM. Pactimibe sulfate (CS-505) possesses anti-atherosclerotic potential with lowering plasma cholesterol activity[2].
Pactimibe sulfate (CS-505) induces moderate ACAT inhibition in monocyte-derived macrophages, leading to the suppression of foam cell formation[2].
Pactimibe sulfate (CS-505; 60 and 200 mg/kg/day; oral gavage; twice a day; 12 weeks) induces an inhibition for ACAT-1 and ACAT-2, causing a reduction of plasma cholesterol but no influence on macrophage- or collagen-positive areas[3].
References:
[1]. Naoki Terasaka, et al. ACAT inhibitor pactimibe sulfate (CS-505) reduces and stabilizes atherosclerotic lesions by cholesterol-lowering and direct effects in apolipoprotein E-deficient mice. Atherosclerosis. 2007 Feb;190(2):239-47.
[2]. Ken Kitayama, et al. Importance of acyl-coenzyme A:cholesterol acyltransferase 1/2 dual inhibition for anti-atherosclerotic potency of pactimibe. Eur J Pharmacol. 2006 Jul 1;540(1-3):121-30.
[3]. Yasunobu Yoshinaka, et al. A selective ACAT-1 inhibitor, K-604, stimulates collagen production in cultured smooth muscle cells and alters plaque phenotype in apolipoprotein E-knockout mice. Atherosclerosis. 2010 Nov;213(1):85-91.
| Cas No. | 608510-47-0 | SDF | |
| 别名 | 帕替麦布,CS-505 | ||
| Canonical SMILES | O=C(O)CC1=C(C)C2=C(N(CCCCCCCC)CC2)C(NC(C(C)(C)C)=O)=C1C.O=S(O)(O)=O.[1/2] | ||
| 分子式 | C25H40N2O3.1/2H2O4S | 分子量 | 465.65 |
| 溶解度 | DMSO : 120 mg/mL (257.70 mM) | 储存条件 | 4°C, away from moisture |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1475 mL | 10.7377 mL | 21.4754 mL |
| 5 mM | 0.4295 mL | 2.1475 mL | 4.2951 mL |
| 10 mM | 0.2148 mL | 1.0738 mL | 2.1475 mL |
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ACAT inhibitor Pactimibe sulfate (CS-505) reduces and stabilizes atherosclerotic lesions by cholesterol-lowering and direct effects in apolipoprotein E-deficient mice
Atherosclerosis 2007 Feb;190(2):239-47.PMID:16626720DOI:10.1016/j.atherosclerosis.2006.03.007.
The objective of the present study was to determine whether a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, Pactimibe sulfate (CS-505), could reduce atherosclerotic lesions beyond and independent of the reduction achieved by cholesterol lowering alone from two different types of lesions. (1) Early lesion model. Twelve-week-old apolipoprotein E (apoE)(-/-) mice were treated with 0.03 or 0.1% (w/w) CS-505, 0.1 or 0.3% avasimibe (CI-1011), or 3% cholestyramine for 12 weeks. Each treatment significantly reduced plasma cholesterol by a similar degree (43-48%). The antiatherosclerotic activity of 0.1% CS-505, however, was more efficacious than the effects of the other treatments (90% versus 40-50%). (2) Advanced lesion model. Twenty-four-week-old apoE(-/-) mice were treated with 0.03 or 0.1% CS-505 or 0.1% CI-1011 for 12 weeks. CS-505 at 0.1% revealed enhanced lesion reduction compared with 0.1% CI-1011 (77% versus 54%), whereas the plasma cholesterol-lowering effect of 0.1% CS-505 was almost the same as that of 0.1% CI-1011. Furthermore, immunohistochemical analysis demonstrated that CS-505 significantly reduced the number of macrophages and expression of matrix metalloproteinase (MMP)-2, MMP-9, and MMP-13. These data indicate that CS-505 can reduce and stabilize atherosclerotic lesions. This antiatherosclerotic activity is exerted via both cholesterol lowering and direct ACAT inhibition in plaque macrophages.
Effects of ketoconazole and quinidine on pharmacokinetics of pactimibe and its plasma metabolite, R-125528, in humans
Drug Metab Dispos 2008 Aug;36(8):1505-11.PMID:18448569DOI:10.1124/dmd.108.021394.
Pactimibe sulfate is a novel acyl coenzyme A:cholesterol acyltransferase inhibitor developed for the treatment of hypercholesterolemia and atherosclerotic diseases. Pactimibe has two equally dominant clearance pathways forming R-125528 by CYP3A4 and M-1 by CYP2D6 in vitro. R-125528 is a plasma metabolite and is cleared solely by CYP2D6 despite its acidity. To evaluate contributions of the cytochrome P450 enzymes on the pharmacokinetics of pactimibe and R-125528 in humans, drug-drug interaction studies using ketoconazole and quinidine were conducted. Eighteen healthy male subjects were given a single dose of Pactimibe sulfate without and with 400 mg of ketoconazole (q.d.). With the concomitant treatment, the area under the plasma concentration-time curve (AUC(0-inf)) of pactimibe modestly increased 1.7-fold and AUC(0-tz) of R-125528 decreased by 55%. In addition, 17 healthy male subjects were given a single dose of Pactimibe sulfate without and with 600 mg of quinidine (b.i.d.). With the concomitant treatment, the AUC(0-inf) for pactimibe modestly increased 1.7-fold. On the other hand, the AUC(0-tz) of R-125528 was markedly elevated 5.0-fold, although the AUC(0-inf) could not be adequately defined because the terminal elimination phase of R-125528 was not obtained in the study period up to 72 h. As the f(m CYP3A4) and f(m CYP2D6) values of pactimibe estimated from in vitro studies were 0.40 and 0.33, respectively, AUC increase ratios of pactimibe were estimated to be 1.7 with ketoconazole and 1.5 with quinidine. These values were well in accordance with the values observed in this study. Moreover, the f(m CYP2D6) of R-125528 estimated to be almost 1 would well explain the accumulation of R-125528 observed with the quinidine treatment.
Effect of CYP2D6 polymorphism on pharmacokinetics of a novel ACAT inhibitor, pactimibe and its unique metabolite, R-125528
Int J Clin Pharmacol Ther 2008 Nov;46(11):545-55.PMID:19000552DOI:10.5414/cpp46545.
Purpose: Pactimibe is a novel ACAT inhibitor. The pharmacokinetics of pactimibe and its pharmacologically inactive plasma metabolite, R-125528, of which the main clearance pathway is CYP2D6, was affected by coadministration of quinidine. The aim of this study was to investigate the influence of CYP2D6 polymorphism on pharmacokinetics of pactimibe and R-125528. In addition, exposure was examined after multiple doses of Pactimibe sulfate in CYP2D6 poor metabolizer (PMs). Methods: 24 healthy male Caucasian volunteers, genotyped as extensive, intermediate, and poor metabolizers, were received single dose of 25 mg pactimibe. In a multiple-dose study, six CYP2D6 PMs received 100 mg pactimibe for 21 days and exposure of pactimibe and R-125528 was examined. Results: In contrast to the mild 1.7-fold increase in AUC0-inf of pactimibe, a marked 3.1-fold increase in AUC0-tz of R-125528 was observed in CYP2D6 PMs. After multiple doses of 100 mg pactimibe to CYP2D6 PMs, the accumulation ratio of R-125528 reached 8.8-fold, however, the exposure of R-125528 in CYP2D6 PMs was covered by the exposure in additional metabolite safety testing. Conclusions: Although CYP2D6 polymorphism greatly affected the pharmacokinetics of R-125528 rather than pactimibe, the exposure in CYP2D6 PMs after a multiple dose of 100 mg Pactimibe sulfate was covered by additional non-clinical metabolite safety testing. The finding is clinically informative with respect to the safety testing of drug metabolite present at disproportionately high levels in a special population with specific genetic back ground.
Importance of acyl-coenzyme A:cholesterol acyltransferase 1/2 dual inhibition for anti-atherosclerotic potency of pactimibe
Eur J Pharmacol 2006 Jul 1;540(1-3):121-30.PMID:16730694DOI:10.1016/j.ejphar.2006.04.022.
Pactimibe sulfate, [7-(2,2-dimethylpropanamido)-4,6-dimethyl-1-octylindolin-5-yl]acetic acid hemisulfate, a novel Acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibitor, was investigated in vitro and in vivo to characterize its potential. Pactimibe exhibited dual inhibition for ACAT1 and ACAT2 (concentrations inhibiting 50% [IC50s] at micromolar levels) more potently than avasimibe. Kinetic analysis revealed pactimibe is a noncompetitive inhibitor of oleoyl-CoA (Ki value: 5.6 microM). Furthermore, pactimibe markedly inhibited cholesteryl ester formation (IC50: 6.7 microM) in human monocyte-derived macrophages, and inhibited copper-induced oxidation of low density lipoprotein more potently than probucol. Pactimibe exerted potent lipid-lowering and anti-atherosclerotic effects in atherogenic diet-fed hamsters. At doses of 3 and 10 mg/kg for 90 days, pactimibe decreased serum total cholesterol by 70% and 72%, and aortic fatty streak area by 79% and 95%, respectively. Despite similar cholesterol lowering, fatty streak area reduction was greater by 10 mg/kg. These results suggest that ACAT1/2 dual inhibitor pactimibe has anti-atherosclerotic potential beyond its plasma cholesterol-lowering activity.
CYP2D6-Mediated metabolism of a novel acyl coenzyme A:cholesterol acyltransferase inhibitor, pactimibe, and its unique plasma metabolite, R-125528
Drug Metab Dispos 2008 Mar;36(3):529-34.PMID:18056254DOI:10.1124/dmd.107.018853.
Pactimibe sulfate is a novel acyl coenzyme A:cholesterol acyltransferase inhibitor. We conducted metabolic studies of pactimibe and its plasma metabolite, R-125528. Pactimibe had multiple metabolic pathways including indolin oxidation to form R-125528, omega-1 oxidation, N-dealkylation, and glucuronidation. Among them, the indolin oxidation and the omega-1 oxidation were dominant and were mainly catalyzed by CYP3A4 and CYP2D6, respectively. The intrinsic clearance (CL(int)) values for these pathways in human hepatic microsomes were 0.63 and 0.76 microl/min/mg-protein, respectively. On the other hand, the metabolic reaction for R-125528 was restricted. It was demonstrated that omega-1 oxidation was the only pathway that could eliminate R-125528 from the systemic circulation. To our surprise, only CYP2D6-expressing microsomes could catalyze the reaction, and omega-1 oxidation was strongly correlated with the CYP2D6 marker reaction, dextromethorphan O-demethylation (r(2) = 0.90), in human hepatic microsomes. Although R-125528 is an atypical substrate for CYP2D6 because of its acidity, the K(m) value was 1.8 microM for the reaction in human hepatic microsomes and the CL(int) value was as high as 75.0 microl/min/mg-protein. These results suggested that the systemic clearance of R-125528 was highly dependent on CYP2D6 activity and that several studies with CYP2D6 including drug-drug interaction and polymorphism sensitivity should be performed during development from the viewpoint of metabolite safety assessment. The finding that R-125528, an acidic compound devoid of basic nitrogen, was a good substrate for CYP2D6 raised a question about previously reported CYP2D6 models based on a critical electrostatic interaction with Asp(301) and/or Glu(216).