MK-0354
目录号 : GC32464
MK-0354是特异性的GPR109a受体激动剂,作用于hGPR109a/mGPR109a,EC50分别为1.65μM和1.08μM,对GPR109b没有作用效果。
Cas No.:851776-28-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
MK-0354 is a partial agonist of GPR109a receptor, for hGPR109a/ mGPR109a with EC50 of 1.65/1.08 μM, showed no activation of GPR109b.IC50 value: 1.65 μM (EC50, for hGPR109a), 1.08 μM (EC50, for mGPR109a) [1]Target: GPR109ain vitro: MK-0354 demonstrated clear and statistically significant partial agonism in the cAMP assays for both the mouse and human receptors with efficacy approximately 60-70% of that of either nicotinic acid or β-hydroxy butyrate, a putative physiologically relevant ligand for hGPR109a, in the same assay platform. In addition, MK-0354 showed no activation of GPR109b in the cAMP assay at any concentration up to 100 μM. Following these interesting observations, we then prepared a number of other 5,5-fused pyrazoles analogous to those that showed receptor activity in our earlier studies. MK-0354 appeared to be somewhat unique among the members of the pyrazole tetrazole series in having reasonable receptor activity.[1]in vivo: MK-0354 retained the plasma free fatty acid lowering effects in mice associated with GPR109a agonism, but did not induce vasodilation at the maximum feasible dose. Moreover, preadministration of MK-0354 blocked the flushing effect induced by nicotinic acid but not that induced by PGD2. This profile made MK-0354 a suitable candidate for further study for the treatment of dyslipidemia.[1] MK-0354 is a GPR109A partial agonist that activates the antilipolytic pathway in adipocytes. The single-dose and multiple-dose pharmacokinetics and pharmacodynamics, as well as tolerability, of MK-0354 were examined in two Phase I studies conducted in healthy male volunteers. The lipid efficacy of MK-0354 was assessed in a Phase II study conducted in male and female patients with dyslipidemia.[2]
[1]. Semple G, et al. 3-(1H-Tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole (MK-0354): A Partial Agonist of the Nicotinic Acid Receptor, G-Protein Coupled Receptor 109a, with Antilipolytic but No Vasodilatory Activity in Mice. J. Med. Chem., 2008, 51 (16) [2]. Lai E1, et al. Effects of a niacin receptor partial agonist, MK-0354, on plasma free fatty acids, lipids, and cutaneous flushing in humans. J Clin Lipidol. 2008 Oct;2(5):375-383.
| Cas No. | 851776-28-8 | SDF | |
| Canonical SMILES | C12=C(CCC2)C(C3=NN=NN3)=NN1 | ||
| 分子式 | C7H8N6 | 分子量 | 176.18 |
| 溶解度 | DMSO : ≥ 36 mg/mL (204.34 mM) | 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。 |
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1 mg | 5 mg | 10 mg |
| 1 mM | 5.676 mL | 28.3801 mL | 56.7601 mL |
| 5 mM | 1.1352 mL | 5.676 mL | 11.352 mL |
| 10 mM | 0.5676 mL | 2.838 mL | 5.676 mL |
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Effects of a niacin receptor partial agonist, MK-0354, on plasma free fatty acids, lipids, and cutaneous flushing in humans
J Clin Lipidol 2008 Oct;2(5):375-83.PMID:21291763DOI:10.1016/j.jacl.2008.08.445.
Background: Development of niacin-like agents that favorably affect lipids with an improved flushing profile would be beneficial. Objective: To evaluate a niacin receptor partial agonist, MK-0354, in Phase I and II studies. Methods: The pharmacokinetic/pharmacodynamic effects of single and multiple doses (7 days) of MK-0354 (300-4000 mg) were evaluated in two Phase I studies conducted in healthy men. A Phase II study assessed the effects of MK-0354 2.5 g once daily on lipids during 4 weeks in 66 dyslipidemic patients. Results: MK-0354 single doses up to 4000 mg and multiple doses (7 days) up to 3600 mg produced robust dose-related reductions in free fatty acid (FFA) over 5 hours. Single doses of MK-0354 300 mg and extended release-niacin (Niaspan) 1 g produced comparable reductions in FFA. Suppression of FFA following 7 daily doses of MK-0354 was similar to that after a single dose. In the Phase II study, MK-0354 2.5 g produced little flushing but no clinically meaningful effects on lipids (placebo-adjusted percent change: high-density lipoprotein cholesterol, 0.4%, 95% confidence interval -5.2 to 6.0; low-density lipoprotein cholesterol, -9.8%, 95% confidence interval -16.8 to -2.7; triglyceride, -5.8%, 95% confidence interval -22.6 to 11.9). Conclusion: Treatment with MK-0354 for 7 days resulted in plasma FFA suppression with minimal cutaneous flushing. However, 4 weeks of treatment with MK-0354 failed to produce changes in high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, or triglycerides.
3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole (MK-0354): a partial agonist of the nicotinic acid receptor, G-protein coupled receptor 109a, with antilipolytic but no vasodilatory activity in mice
J Med Chem 2008 Aug 28;51(16):5101-8.PMID:18665582DOI:10.1021/jm800258p.
The discovery and profiling of 3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole (5a, MK-0354), a partial agonist of GPR109a, is described. Compound 5a retained the plasma free fatty acid lowering effects in mice associated with GPR109a agonism, but did not induce vasodilation at the maximum feasible dose. Moreover, preadministration of 5a blocked the flushing effect induced by nicotinic acid but not that induced by PGD2. This profile made 5a a suitable candidate for further study for the treatment of dyslipidemia.
HM74a agonists: will they be the new generation of nicotinic acid?
Curr Top Med Chem 2009;9(5):428-35.PMID:19519459DOI:10.2174/156802609788340814.
The discovery of HM74a as a high affinity receptor for nicotinic acid has opened up new areas for investigation. Since its discovery, several new chemical entities have been reported as HM74a agonists. One of them, MK-0354, has been tested in phase II studies, but despite significant decreases in Free Fatty Acid levels with absence of flushing events in clinical studies, it failed to demonstrate effects on LDL-Cholesterol, Triglycerides and HDL-Cholesterol. These surprising results lead to questions about the reality of HM74a as the unique receptor responsible for the lipid modulating effects of nicotinic acid. This review summarizes these recent developments, and the novel HM74a antagonist structures recently published.
Novel patent publications on high-affinity nicotinic acid receptor agonists
Expert Opin Ther Pat 2009 Jul;19(7):957-67.PMID:19552512DOI:10.1517/13543770902991526.
Background: Nicotinic acid (NA) has been used as a drug to treat dyslipidemia for > 50 years. In outcome clinical trials, NA displayed remarkable efficacy in patients with cardiovascular diseases by modifying lipid profiles that results in reduced morbidity and mortality. On the other hand, NA induces vasodilation (flushing) that undermines treatment compliance. In addition, high-dose treatment is required presumably owing to the poor pharmacokinetic properties of NA. The identification of the high-affinity NA receptor, namely G-protein coupled receptor 109A (GPR109A), led to further understanding of the pharmacological effects of NA and discovery of compounds that are potentially superior in efficacy yet devoid of NA's adverse effects. Objective/method: This review focuses on the endeavors of several pharmaceutical companies to discover and develop GPR109A agonists. Representative compounds of each series in patent literature since 2005 are highlighted. Conclusion: Highly potent GPR109A agonists with minimal flushing effects and robust free fatty acid reduction have been identified. Despite the failure of the partial agonist MK-0354 to achieve efficacy in a Phase II clinical trial, at least three other GPR109A agonists have been evaluated in clinical trials. The upcoming clinical data would be critical to validate the therapeutic utility of this receptor.
Differential tissue and ligand-dependent signaling of GPR109A receptor: implications for anti-atherosclerotic therapeutic potential
Cell Signal 2013 Oct;25(10):2003-16.PMID:23770183DOI:10.1016/j.cellsig.2013.06.008.
Until recently, the anti-atherosclerotic effects of niacin were attributed primarily to its lipid modification properties mediated by adipocyte G-protein coupled receptor GPR109A, though recent studies have raised significant doubts about this mechanism. In fact, in rodents it has recently been demonstrated that niacin inhibits progression of atherosclerosis through actions on immune cells, particularly via macrophage-expressed GPR109A, independent of lipid-modifying properties. Here, we studied GPR109A signal transduction in human Langerhans cells, macrophages and adipocytes. We find that the consequences of receptor activation are profoundly influenced by cellular context and that ligand-biased signaling significantly impacts functionally relevant signaling. In Langerhans cells, niacin initiates GPR109A-mediated signaling pathways (Erk1/2 and Ca(2+)) responsible for the release of vasodilatory prostanoids, while the synthetic GPR109A agonist MK-0354 fails to elicit any signaling, providing a mechanistic basis for the latter compound's inability to cause flushing. While GPR109A mediates inhibition of cAMP in adipocytes, in macrophages GPR109A signaling via G尾纬 subunits results in paradoxical augmentation of intracellular cAMP levels. Also, in macrophages niacin and GPR109A full agonists induce Erk1/2 and Ca(2+) signaling, release of prostanoids, upregulation of cholesterol transporters ABCA1 and ABCG1 and stimulation of reverse cholesterol transport in GPR109A dependent manner. A mechanism is presented in which signals from the autocrine action of released prostanoids and Gi protein mediated cAMP augmentation are integrated leading to modulation of reverse cholesterol transport regulatory components. These studies provide key insights into mechanisms by which GPR109A may influence cholesterol efflux in macrophages; a process that may be at least partially responsible for niacin's anti-atherosclerotic activity. MK-0354 does not induce niacin-like GPR109A signaling in macrophages, suggesting that biased agonists devoid of the flushing side-effect may also lack properties required for macrophage-mediated anti-atherosclerotic effects.