阿帕他隆

阿帕他隆,RVX 208(1044870-39-4),危害标识：

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信号	Warning
GHS危险说明	Aggregated GHS information provided by 92 companies from 1 notifications to the ECHA C&L Inventory.
	H371 (100%): May cause damage to organs [Warning Specific target organ toxicity, single exposure]
	Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.
	P260, P264, P270, P309+P311, P405, and P501
防范说明代码	(The corresponding statement to each P-code can be found at the GHS Classification page.)

McLure KG1，Gesner EM1，Tsujikawa L1，Kharenko OA1，Attwell S1，Campeau E1，Wasiak S1，Stein A2，White A2，Fontano E2，Suto RK2，Wong NC1，Wagner GS1，Hansen HC1，Young PR1。PLoS一。2013年12月31日; 8（12）：e83190。doi：10.1371 / journal.pone.0083190。eCollection 2013。
Increased synthesis of Apolipoprotein A-I (ApoA-I) and HDL is believed to provide a new approach to treating atherosclerosis through the stimulation of reverse cholesterol transport. RVX-208 increases the production of ApoA-I in hepatocytes in vitro, and in vivo in monkeys and humans, which results in increased HDL-C, but the molecular target was not previously reported. Using binding assays and X-ray crystallography, we now show that RVX-208 selectively binds to bromodomains of the BET (Bromodomain and Extra Terminal) family, competing for a site bound by the endogenous ligand, acetylated lysine, and that this accounts for its pharmacological activity. siRNA experiments further suggest that induction of ApoA-I mRNA is mediated by BET family member BRD4. These data indicate that RVX-208 increases ApoA-I production through an epigenetic mechanism and suggests that BET inhibition may be a promising new approach to the treatment of atherosclerosis.

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2.RVX-208是一种用于治疗动脉粥样硬化性心血管疾病的BET抑制剂，可升高ApoA-I / HDL并抑制导致心血管疾病的途径。
Gilham D1，Wasiak S1，Tsujikawa LM1，Hallibay C1，Norek K1，Patel RG1，Kulikowski E1，Johansson J2，Sweeney M2，Wong NC3。动脉粥样硬化。2016年4月; 247：48-57。doi：10.1016 / j。动脉粥样硬化.2016.01.036。EPUB 2016年1月22日。
High density lipoproteins (HDL), through activity of the main protein component apolipoprotein A-I (ApoA-I), can reduce the risk of cardiovascular disease (CVD) by removing excess cholesterol from atherosclerotic plaque. In this study, we demonstrate that the bromodomain and extraterminal domain (BET) inhibitor RVX-208 increases ApoA-I gene transcription and protein production in human and primate primary hepatocytes. Accordingly, RVX-208 also significantly increases levels of ApoA-I, HDL-associated cholesterol, and HDL particle number in patients who received the compound in recently completed phase 2b trials SUSTAIN and ASSURE. Moreover, a post-hoc analysis showed lower instances of major adverse cardiac events in patients receiving RVX-208. To understand the effects of RVX-208 on biological processes underlying cardiovascular risk, we performed microarray analyses of human primary hepatocytes and whole blood treated ex vivo. Overall, data showed that RVX-208 raises ApoA-I/HDL and represses pro-inflammatory, pro-atherosclerotic and pro-thrombotic pathways that can contribute to CVD risk.

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3.评估RVX-208用于治疗动脉粥样硬化。
Nikolic D1，Rizzo M1,2，Mikhailidis DP3，Wong NC4，Banach M5。专家Opin调查药物。2015; 24（10）：1389-98。doi：10.1517 / 13543784.2015.1083010。
INTRODUCTION: RVX-208 is a first-in-class, orally active, novel small molecule in development by Resverlogix Corporation (Calgary, AB, Canada). It acts through an epigenetic mechanism by inhibiting the bromodomain and extraterminal (BET) family of proteins, increasing apolipoprotein A-I (apoA-I) and targeting high-density lipoprotein (HDL) metabolism, including generating of nascent HDL and increased larger HDL particles, resulting in the stimulation of reverse cholesterol transport. RVX-208 also has a beneficial effect on inflammatory factors known to be involved in atherosclerosis and plaque stability. New therapeutic strategies are needed for patients with atherosclerosis.

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4，一种新的BET溴结构域抑制剂RVX-208在高脂血症ApoE缺陷小鼠中显示出动脉粥样硬化的减少。
Jahagirdar R1，Zhang H2，Azhar S2，Tobin J3，Attwell S3，Yu R3，Wu J3，McLure KG3，Hansen HC3，Wagner GS3，Young PR3，Srivastava RA4，Wong NC3，Johansson J3。动脉粥样硬化。2014年9月; 236（1）：91-100。doi：10.1016 / j。动脉粥样硬化。2014.06.008。EPUB 2014年6月28日。
Despite the benefit of statins in reducing cardiovascular risk, a sizable proportion of patients still remain at risk. Since HDL reduces CVD risk through a process that involves formation of pre-beta particles that facilitates the removal of cholesterol from the lipid-laden macrophages in the arteries, inducing pre-beta particles, may reduce the risk of CVD. A novel BET bromodomain antagonist, RVX-208, was reported to raise apoA-I and increase preβ-HDL particles in non-human primates and humans. In the present study, we investigated the effect of RVX-208 on aortic lesion formation in hyperlipidemic apoE(-/-) mice. Oral treatments of apoE(-/-) mice with 150 mg/kg b.i.d RVX-208 for 12 weeks significantly reduced aortic lesion formation, accompanied by 2-fold increases in the levels of circulating HDL-C, and ∼50% decreases in LDL-C, although no significant changes in plasma apoA-I were observed. Circulating adhesion molecules as well as cytokines also showed significant reduction.