MK-7145
目录号 : GC32646
MK-7145是ROMK的一个抑制剂，其IC50值为0.045μM。
Cas No.:1255204-84-2
Sample solution is provided at 25 µL, 10mM.
;)
,-1-7$$$37316672.jpg');)
;)
;)
$$$36806353.jpg');)
;33(7)%EF%BC%9A546-561$$$37156877.jpg');)
;)
;)
;)
%201124-1138.$$$35908550.jpg');)
%20766-780.$$$37100057.jpg');)
%20418-432.$$$36893736.jpg');)
%EF%BC%9A-240-255.$$$35108512.jpg');)
533-545$$$36543525.jpg');)
%201-13.$$$36600053.jpg');)
;)
Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
MK-7145 is a ROMK inhibitor, with an IC50 of 0.045 μM.
MK-7145 (Compound 12) is screened against other members of the Kir family of channels. It doed not show any significant activity on Kir2.1, Kir2.3, Kir4.1, or Kir7.1 channels when tested at concentrations up to 30 μM. MK-7145 is also selective against other cardiac ion channels such as Cav1.2 and Nav1.5 (IC50>30 μM). In a broad counterscreen panel conducted at Panlabs and including over 150 receptors, enzymes, and ion channels, MK-7145 only exhibits three activities at <10 μM: acetyl cholinesterase, ACES, IC50=9.94 μM, somatostatin subtype 1, sst1 IC50=2.63 μM, and human serotonin transporter, SERT, IC50=0.12 μM. In a functional assay using HEK293 cells stably transfected with human SERT, uptake of 3H-serotonin is inhibited by MK-7145 with an IC50 value of 2.40±0.32 μM (n=5). The superior ROMK potency and in vivo efficacy of MK-7145, coupled with the fact that MK-7145 is a substrate of human Pgp (human Mdr1 BAAB ratio=12), should be able to impart a significant safety window with respect to the SERT off-target activity.
[1]. Tang H, et al. Discovery of MK-7145, an Oral Small Molecule ROMK Inhibitor for the Treatment of Hypertension and Heart Failure. ACS Med Chem Lett. 2016 May 12;7(7):697-701.
| Cas No. | 1255204-84-2 | SDF | |
| Canonical SMILES | O[C@H](C1=C(C)C2=C(C(OC2)=O)C=C1)CN3CCN(C[C@@H](C4=C(C)C5=C(C(OC5)=O)C=C4)O)CC3 | ||
| 分子式 | C26H30N2O6 | 分子量 | 466.53 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| 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。 |
||
| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 2.1435 mL | 10.7174 mL | 21.4348 mL |
| 5 mM | 0.4287 mL | 2.1435 mL | 4.287 mL |
| 10 mM | 0.2143 mL | 1.0717 mL | 2.1435 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Discovery of MK-7145, an Oral Small Molecule ROMK Inhibitor for the Treatment of Hypertension and Heart Failure
ACS Med Chem Lett 2016 May 12;7(7):697-701.PMID:27437080DOI:10.1021/acsmedchemlett.6b00122.
ROMK, the renal outer medullary potassium channel, is involved in potassium recycling at the thick ascending loop of Henle and potassium secretion at the cortical collecting duct in the kidney nephron. Because of this dual site of action, selective inhibitors of ROMK are expected to represent a new class of diuretics/natriuretics with superior efficacy and reduced urinary loss of potassium compared to standard-of-care loop and thiazide diuretics. Following our earlier work, this communication will detail subsequent medicinal chemistry endeavors to further improve lead selectivity against the hERG channel and preclinical pharmacokinetic properties. Pharmacological assessment of highlighted inhibitors will be described, including pharmacodynamic studies in both an acute rat diuresis/natriuresis model and a subchronic blood pressure model in spontaneous hypertensive rats. These proof-of-biology studies established for the first time that the human and rodent genetics accurately predict the in vivo pharmacology of ROMK inhibitors and supported identification of the first small molecule ROMK inhibitor clinical candidate, MK-7145.
The Renal Outer Medullary Potassium Channel Inhibitor, MK-7145, Lowers Blood Pressure, and Manifests Features of Bartter's Syndrome Type II Phenotype
J Pharmacol Exp Ther 2016 Oct;359(1):194-206.PMID:27432892DOI:10.1124/jpet.116.235150.
The renal outer medullary potassium (ROMK) channel, located at the apical surface of epithelial cells in the thick ascending loop of Henle and cortical collecting duct, contributes to salt reabsorption and potassium secretion, and represents a target for the development of new mechanism of action diuretics. This idea is supported by the phenotype of antenatal Bartter's syndrome type II associated with loss-of-function mutations in the human ROMK channel, as well as, by cardiovascular studies of heterozygous carriers of channel mutations associated with type II Bartter's syndrome. Although the pharmacology of ROMK channels is still being developed, channel inhibitors have been identified and shown to cause natriuresis and diuresis, in the absence of any significant kaliuresis, on acute oral dosing to rats or dogs. Improvements in potency and selectivity have led to the discovery of MK-7145 [5,5'-((1R,1'R)-piperazine-1,4-diylbis(1-hydroxyethane-2,1-diyl))bis(4-methylisobenzofuran-1(3H)-one)], a potential clinical development candidate. In spontaneously hypertensive rats, oral dosing of MK-7145 causes dose-dependent lowering of blood pressure that is maintained during the entire treatment period, and that displays additive/synergistic effects when administered in combination with hydrochlorothiazide or candesartan, respectively. Acute or chronic oral administration of MK-7145 to normotensive dogs led to dose-dependent diuresis and natriuresis, without any significant urinary potassium losses or changes in plasma electrolyte levels. Elevations in bicarbonate and aldosterone were found after 6 days of dosing. These data indicate that pharmacological inhibition of ROMK has potential as a new mechanism for the treatment of hypertension and/or congestive heart failure. In addition, Bartter's syndrome type II features are manifested on exposure to ROMK inhibitors.
Discovery of MK-8153, a Potent and Selective ROMK Inhibitor and Novel Diuretic/Natriuretic
J Med Chem 2021 Jun 10;64(11):7691-7701.PMID:34038119DOI:10.1021/acs.jmedchem.1c00406.
A renal outer medullary potassium channel (ROMK, Kir1.1) is a putative drug target for a novel class of diuretics with potential for treating hypertension and heart failure. Our first disclosed clinical ROMK compound, 2 (MK-7145), demonstrated robust diuresis, natriuresis, and blood pressure lowering in preclinical models, with reduced urinary potassium excretion compared to the standard of care diuretics. However, 2 projected to a short human half-life (∼5 h) that could necessitate more frequent than once a day dosing. In addition, a short half-life would confer a high peak-to-trough ratio which could evoke an excessive peak diuretic effect, a common liability associated with loop diuretics such as furosemide. This report describes the discovery of a new ROMK inhibitor 22e (MK-8153), with a longer projected human half-life (∼14 h), which should lead to a reduced peak-to-trough ratio, potentially extrapolating to more extended and better tolerated diuretic effects.
The therapeutic potential of targeting the Kir1.1 (renal outer medullary K+) channel
Future Med Chem 2017 Oct;9(16):1963-1977.PMID:29076349DOI:10.4155/fmc-2017-0083.
Kir1.1 (renal outer medullary K+) channels are potassium channels expressed almost exclusively in the kidney and play a role in the body's electrolyte and water balance. Potassium efflux through Kir1.1 compliments the role of transporters and sodium channels that are the targets of known diuretics. Consequently, loss-of-function mutations in men and rodents are associated with salt wasting and low blood pressure. On this basis, Kir1.1 inhibitors may have value in the treatment of hypertension and heart failure. Efforts to develop small molecule Kir1.1 inhibitors produced MK-7145, which entered into clinical trials. The present manuscript describes the structure-activity relationships associated with this scaffold alongside other preclinical Kir1.1 blockers.