氯苯唑酸合成路线图解

<正>氯苯唑酸(tafamidis,1)，化学名称为2-(3,5-二氯苯基)-6-苯并噁唑甲酸，分子式为C₁₄H₇Cl₂NO₃，分子量为308.11,CAS登记号为594839-88-0。氯苯唑酸由辉瑞公司开发，于2020年2月在中国获批上市，商品名为维达全(Vyndaqel)，是目前唯一上市的用于治疗转甲状腺素蛋白淀粉样多发性神经病的药物^[1]。转甲状腺素蛋白淀粉样变是由不稳定的转甲状腺素蛋白沉积所导致的一种罕见的系统性疾病，临床特征为进行性周围神经、自主神经病变及不同程度的内脏器官淀粉样蛋白质沉积，常伴有其他脏器功能障碍，如淀粉样心肌病和肾脏病变^[2]。氯苯唑酸是转甲状腺素蛋白稳定剂，通过与转甲状腺素蛋白结合而阻止其分解，进而防止淀粉样蛋白原纤维的形成，从而延缓神经疾病的进展。     

转甲状腺素蛋白心脏淀粉样变心肌病及其合并症的药物治疗进展

转甲状腺素蛋白心脏淀粉样变心肌病（ATTR-CM）是由于不稳定的转甲状腺素蛋白（TTR）四聚体解离成单体后错误折叠为淀粉样物质沉积于心肌间质所致的一种浸润性心肌病。既往针对ATTR-CM无特异性的治疗药物，主要针对心力衰竭和心律失常对症治疗。近年来针对ATTR-CM的发病机制，学者们研发了两大类药物：一类是稳定TTR四聚体结构的药物（如氯苯唑酸和acoramidis），另一类是干扰TTR合成的药物（如patisiran）。其中氯苯唑酸已被研究证实是目前唯一能治疗ATTR-CM的药物，其他药物均尚处于临床试验阶段，临床证据有限。在ATTR-CM合并症的药物治疗方面，主要是针对最常见的心脏合并症（如心力衰竭和心律失常）的治疗；传统用于改善心力衰竭预后的药物（如β受体阻滞剂、肾素-血管紧张素受体拮抗剂）在ATTR-CM患者中未证实可改善预后，相反可能带来不良反应。对于合并房颤的ATTR-CM患者，推荐进行抗凝治疗以预防血栓形成，并可使用胺碘酮进行节律控制。尽管ATTR-CM在药物治疗方面取得了显著进展，但整体预后仍较差，需要在发病机制和靶点开发方面进一步研究，以进一步改善ATTR-CM患者的...     

转甲状腺素蛋白淀粉样变性疾病治疗药物非临床研究评价概述

转甲状腺素蛋白淀粉样变性(transthyretin amyloidosis,ATTR)疾病是由转甲状腺素蛋白(transthyretin,TTR)错误折叠导致其在组织中异常沉积引起的疾病,主要累及外周神经系统和心脏,表现为进行性加重至危及生命.目前,国外已有3个靶向TTR的治疗药物在美国和欧洲上市,其非临床药效学及毒...     

Inotersen sodium (Tegsedi)

<正>Inotersen sodium 是由 Ionis Pharmaceuticals 公司开发的一种转甲状腺素蛋白(TTR)的反义寡核苷酸类药物,用于治疗遗传性转甲状腺素蛋白淀粉样变性(hATTR)。2018 年 4 月,Akcea Therapeutics 公司获得 Ionis Pharmaceuticals 公司授予的全球独家营销权利。2018 年 7 月 6 日,欧盟批准其皮下制剂上市。2018 年 8 月,Akcea Therap     

转甲状腺素蛋白与2型糖尿病

<正>转甲状腺素蛋白(TTR)与2型糖尿病关系密切,TTR通过损伤β细胞、降低胰岛素敏感性、影响激素及脂肪因子代谢,直接或间接导致或加重2型糖尿病;2型糖尿病出现糖、脂、蛋白质代谢紊乱,可通过免疫机制及受体竞争机制影响转甲状腺素蛋白代谢。本文对二者的关系进行综述。     

Effects of Modification of Transthyretin on Diagnosis of Infectious Lung Disease

目的:探讨转甲状腺素(TTR)蛋白含量和化学修饰类型在诊断肺感染性疾病中的作用.方法:(1)测定22例肺感染患者血清和胸腔积液中总蛋白(TP)、白蛋白(ALB)、三酰甘油(TG)、胆周醇(Cho)、载脂蛋白(Apo)A、Apo B、乳酸脱氢酶(LDH)、腺苷脱氨酶(ADA)、葡萄糖(GLU)和TTR等指标水平.(2)基质辅助激光电离飞行时间质谱(MAL-DI-TOF-MS)分析肺感染患者血清和胸腔积液TTR蛋白的化学修饰;作为对照测定16例健康人血清TTR的修饰.结果:(1)胸腔积液TG、Cho、TTR、ApoA、ApoB、TP、ALB和GLU指标水平均明显低于血清,仅ADA指标增高,差异有统计学意义(P＜0.05或P＜0.01).(2)蛋白指标中TTR减低最明显.(3)肺感染患者胸腔积液和血清中只发现两种修饰类型,而无对照组的cysgly-TTR修饰型.结论:血清及胸腔积液中TTR含量和cysgly-TTR的减少,可能作为辅助诊断肺感染指标.     

转甲状腺素蛋白的化学修饰物在肺感染性疾病诊断中的作用

目的:探讨转甲状腺素(TTR)蛋白含量和化学修饰类型在诊断肺感染性疾病中的作用。方法:(1)测定22例肺感染患者血清和胸腔积液中总蛋白(TP)、白蛋白(ALB)、三酰甘油(TG)、胆固醇(Cho)、载脂蛋白(Apo)A、ApoB、乳酸脱氢酶(LDH)、腺苷脱氨酶(ADA)、葡萄糖(GLU)和TTR等指标水平。(2)基质辅助激光电离飞行时间质谱(MALDI-TOF-MS)分析肺感染患者血清和胸腔积液TTR蛋白的化学修饰;作为对照测定16例健康人血清TTR的修饰。结果:(1)胸腔积液TG、Cho、TTR、ApoA、ApoB、TP、ALB和GLU指标水平均明显低于血清,仅ADA指标增高,差异有统计学意义(P<0.05或P<0.01)。(2)蛋白指标中TTR减低最明显。(3)肺感染患者胸腔积液和血清中只发现两种修饰类型,而无对照组的cysgly-TTR修饰型。结论:血清及胸腔积液中TTR含量和cysgly-TTR的减少,可能作为辅助诊断肺感染指标。     

异(口恶)唑青霉素在男性体内的代谢和尿中排泄的药代动力学比较研究

苯甲异恶唑青霉素(OX)、邻氯苯甲异(?)唑青霉素(CX)、双氯苯甲异(?)唑青霉素(DX)和2,6-氟氯苯甲异(?)唑青霉素(FX)是目前临床用于化疗的半合成异(?)唑基青霉素的同系物(如图1)。已知这些青霉素对革蓝氏阳性细菌,包括耐青霉素G的葡萄球菌具有抑制作用。这些药物对酸稳定,适量口服可经胃肠道有效吸收。除了这些药物的化学和生理化学特性而外,迄今已积累了关于它们的生物药物特性的资料,尤其是药代动力学行为的资料。     

本期新旧药名对照

<正> ampicillin氨苄西林(氨苄青霉素、安比西林、氨苄青,Polycillin,Omnipen);aspirin阿司匹林(醋柳酸、乙酰水杨酸,acetylsalicylic acid);chlorhexidine洗必泰(双氯苯双胍己烷、氯苯胍亭,Hibitan-e);cimetidine西咪替丁(甲氰咪胍、甲腈咪胍、甲腈咪胺、西米替丁,Tagamet);cytarabine阿糖胞苷(胞嘧啶阿拉伯糖苷,Ara-C);danazol达那唑(炔羟雄烯唑、断羟雄烯异(口恶)唑);digoxin地高辛(狄戈     

国外异恶唑青霉素的发展概况及合成方法(综述)

异恶唑青霉素是一类带有异恶唑环,对酸和青霉素酶都稳定,可口服和注射使用的半合成青霉素。它们具有如下的化学结构和名称。 6-(3’、5’-双取代-4’-异恶唑甲酰胺基)青霉烷酸目前,作为药物广泛用于临床的异恶唑青霉素,是 R 为苯基,α-氯苯基,2.6-二氯苯基,2-氟,6-氯苯基和 R′都是甲基的。它们的药物通用名称,分别叫作苯唑青霉素(oxacillin,代号 P_(-12),BRL_(-1400)),氯苯唑青霉素(Cloxacillin,代号 BRL-     

TTR kinetic stabilizers and TTR gene silencing: a new era in therapy for familial amyloidotic polyneuropathies

Introduction: Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP) is a rare disease with autosomal dominant transmission due to a point mutation of the TTR gene. By removing the main source of systemic mutant TTR, liver transplantation (LT) has become the reference therapy of this severe and fatal polyneuropathy of adult-onset, stopping disease progression in subgroup of patients. Recently, new therapeutic strategies have emerged, which intend to stabilize TTR or to silence the TTR gene. Amongst them, the TTR kinetic stabilizer tafamidis is the first drug approved in the EU.

Areas covered: We shall review the natural history of TTR-FAP and the best indications for LT. Data on the efficacy, safety and tolerability of the TTR kinetic stabilizers, tafamidis and diflunisal, have been reviewed, from the pivotal Phase III clinical trials published in PubMed medical journals or presented at international meetings. We will review the ongoing phase III clinical trials of TTR gene silencing with RNAi therapeutics and ASO published in clinicaltrialgov.

Expert opinion: Due to the data on efficacy, tolerability, safety, tafamidis and diflunisal became the first line anti-amyloid treatment in stage 1 TTR-FAP. Both drugs slow progression of the disease. Only tafamidis got marketing authorization. We are waiting for results of the 2 phase III clinical trials of TTR gene silencing in varied stages of the disease.     

Tafamidis for transthyretin amyloidosis

Tafamidis meglumine (Vyndaqel?, Pfizer) is a novel, first-in-class drug for the treatment of transthyretin familial amyloid polyneuropathy (TTR-FAP), a rare neurodegenerative disorder characterized by progressive sensory, motor and autonomic impairment that is ultimately fatal. Pathogenic mutations in the transthyretin (TTR) protein lead to destabilization of its tetrameric structure and subsequent formation of amyloid aggregates. Tafamidis is a small-molecule inhibitor that binds selectively to TTR in human plasma and kinetically stabilizes the tetrameric structure of both wild-type TTR and a number of different mutants. Clinical trials indicate that tafamidis slows disease progression in patients with TTR-FAP and reduces the burden of disease, demonstrating improvement in small and large nerve fiber function, modified body mass index and lower extremity neurological examination. Tafamidis has been granted marketing authorization by the European Commission for the treatment of TTR-FAP and the U.S. Food and Drug Administration is currently reviewing this drug for the same indication.     

The effect of tafamidis on the QTc interval in healthy subjects

Aims

The transthyretin (TTR) stabilizer, tafamidis, has demonstrated efficacy and safety in the treatment of TTR familial amyloid polyneuropathy (20 mg day⁻¹). Tafamidis use in TTR cardiomyopathy led to the study of the potential effect of tafamidis on the QT_c interval in healthy subjects.

Methods

This randomized, three treatment, three period, six sequence crossover study with placebo, a positive control (moxifloxacin 400 mg) and tafamidis (400 mg, to achieve a supra-therapeutic C_max of ∽20 µg ml⁻¹) was conducted in healthy volunteers at three clinical research units. Oral dosing in each of the three treatment periods was separated by a washout period of  ≥ 14 days. Serial triplicate 12-lead electrocardiograms were performed. QT_c intervals were derived using the Fridericia correction method. Safety and tolerability were assessed by physical examination, vital signs measurement, laboratory analyses and monitoring of adverse events (AEs).

Results

A total of 42 subjects completed the study. The upper limit of the two-sided 90% confidence intervals (CIs) for the difference in baseline-adjusted QT_cF between tafamidis 400 mg and placebo was <10 ms (non-inferiority criterion) for all time points. The lower limit of the two-sided 90% CI between moxifloxacin 400 mg and placebo exceeded 5 ms at the pre-specified moxifloxacin t_max of 3 h post-dose, confirming assay sensitivity. C_max and AUC(0,24 h) for tafamidis were 20.36 µg ml⁻¹ and 305.4 µg ml⁻¹ h, respectively. There were no serious/severe AEs or treatment discontinuations due to AEs.

Conclusions

This thorough QT_c study suggests that a supra-therapeutic single 400 mg oral dose of tafamidis does not prolong the QT_c interval and is well-tolerated in healthy volunteers.     

Transthyretin deposition in familial amyloidotic polyneuropathy

The subject of the review is on hereditary transthyretin (TTR) amyloidosis which is a genetically transmitted disease that results from a mutation in the gene encoding the plasma TTR protein. TTR is a transport protein for thyroid hormones and vitamin A and is predominantly synthesised in the liver. Although originally regarded as a rare disease, it is now becoming clear that many kindreds exist worldwide. Current knowledge and hypotheses on the biology of TTR, mechanisms of TTR amyloid fibril formation, phenotypic consequences TTR amyloid deposition and pre-clinical models of the disease will be discussed.     

Small transthyretin (TTR) ligands as possible therapeutic agents in TTR amyloidoses

In transthyretin (TTR) amyloidosis TTR variants deposit as amyloid fibrils giving origin, in most cases, to peripheral polyneuropathy, cardiomyopathy, carpal tunnel syndrome and/or amyloid deposition in the eye. More than eighty TTR variants are known, most of them being pathogenic. The mechanism of TTR fibril formation is still not completely elucidated. However it is widely accepted that the amino acid substitutions in the TTR variants contribute to a destabilizing effect on the TTR tetramer molecule, which in particular conditions dissociate into non native monomeric intermediates that aggregate and polymerize in amyloid fibrils that further elongate. Since this is a multi-step process there is the possibility to impair TTR amyloid fibril formation at different stages of the process namely by tetramer stabilization, inhibition of fibril formation or fibril disruption. Till now the only efficient therapy available is liver transplant when performed in an early phase of the onset of the disease symptoms. Since this is a very invasive therapy alternatives are desirable. In that sense, several compounds have been proposed to impair amyloid formation or disruption. Based on the proposed mechanism for TTR amyloid fibril formation we discuss the action of some of the proposed TTR stabilizers such as derivatives of some NSAIDs (diflunisal, diclofenac, flufenamic acid, and derivatives) and the action of amyloid disrupters such as 4'-iodo-4'-deoxydoxorubicin (I-DOX) and tetracyclines. Among all these compounds, TTR stabilizers seem to be the most interesting since they would impair very early the process of amyloid formation and could also have a prophylactic effect.     

Neurodegeneration in familial amyloidotic polyneuropathy

Familial amyloid polyneuropathies (FAP) constitute a group of inherited amyloidoses that affect peripheral nerves. One common form of FAP is caused by transthyretin (TTR) misfolding and deposition in the peripheral nervous system, leading to neuronal toxicity and death. The molecular mechanisms responsible for this toxicity are unclear; however, there is good biochemical and histopathological evidence that the toxicity of TTR mutations is correlated to their aggregation state. In addition, neuronal calcium dysregulation is a mechanism that has been suggested to drive the pathogenesis of FAP. Amyloidogenic TTR mutations cause significant calcium influx via L-type calcium channels in neuronal cell lines, while in primary sensory neurons, TTR mediates a calcium influx via a novel mechanism of transient receptor potential melanostatin (TRPM8) and voltage-gated sodium and calcium channel activation. Significantly, calcium dysregulation is a pathological hallmark of other neurodegenerative diseases involving amyloidosis, for example Alzheimer's disease, and this mechanism could explain the molecular events that drive amyloid toxicity in other neurodegenerative diseases.     

Synthesis, structure, and activity of diclofenac analogues as transthyretin amyloid fibril formation inhibitors.

Twelve analogues of diclofenac (1), a nonsteroidal antiinflammatory drug and known inhibitor of transthyretin (TTR) amyloid formation, were prepared and evaluated as TTR amyloid formation inhibitors. High activity was exhibited by five of the compounds. Structure-activity relationships reveal that a carboxylic acid is required for activity, but changes in its position as well as the positions of other substituents are tolerated. High-resolution X-ray crystal structures of four of the active compounds bound to TTR were obtained. These demonstrate the significant flexibility with which TTR can accommodate ligands within its two binding sites.     

Advances in the treatment of transthyretin cardiac amyloidosis: Current and emerging therapies

Transthyretin cardiac amyloidosis (ATTR-CA) has been recognized as an underdiagnosed and undertreated cause of heart failure with often unrecognized multiorgan involvement. Guideline development and the establishment of nonbiopsy criteria for diagnosis of ATTR-CA have led to an increased rate of diagnosis and hence patients referred for therapies. ATTR is a protein misfolding disorder where the TTR tetramer disassociates into monomers which form insoluble amyloid depositions in organs, including the heart. ATTR-CA can be due to autosomal dominant transmitted gene mutation or due to misfolding of wild-type TTR. Prior to 2019, there were no FDA-approved pharmacological treatments for ATTR-CA. Understanding of ATTR-CA pathogenesis has enabled development of targeted strategies with novel disease-modifying therapies. Current and emerging therapies for ATTR-CA include (1) TTR gene silencing (siRNA, ASO, CRISPR/Cas9), (2) TTR tetramer stabilization, and (3) TTR amyloid fibril degradation. This review focuses on the pathophysiology of ATTR-CA, diagnostic criteria, and addresses current and emerging treatments for this diverse disorder.     

Diflunisal analogues stabilize the native state of transthyretin. Potent inhibition of amyloidogenesis

Analogues of diflunisal, an FDA-approved nonsteroidal antiinflammatory drug (NSAID), were synthesized and evaluated as inhibitors of transthyretin (TTR) aggregation, including amyloid fibril formation. High inhibitory activity was observed for 26 of the compounds. Of those, eight exhibited excellent binding selectivity for TTR in human plasma (binding stoichiometry >0.50, with a theoretical maximum of 2.0 inhibitors bound per TTR tetramer). Biophysical studies reveal that these eight inhibitors dramatically slow tetramer dissociation (the rate-determining step of amyloidogenesis) over a duration of 168 h. This appears to be achieved through ground-state stabilization, which raises the kinetic barrier for tetramer dissociation. Kinetic stabilization of WT TTR by these eight inhibitors is further substantiated by the decreasing rate of amyloid fibril formation as a function of increasing inhibitor concentration (pH 4.4). X-ray cocrystal structures of the TTR.18(2) and TTR.20(2) complexes reveal that 18 and 20 bind in opposite orientations in the TTR binding site. Moving the fluorines from the meta positions in 18 to the ortho positions in 20 reverses the binding orientation, allowing the hydrophilic aromatic ring of 20 to orient in the outer binding pocket where the carboxylate engages in favorable electrostatic interactions with the epsilon-ammonium groups of Lys 15 and 15'. The hydrophilic aryl ring of 18 occupies the inner binding pocket, with the carboxylate positioned to hydrogen bond to the serine 117 and 117' residues. Diflunisal itself appears to occupy both orientations based on the electron density in the TTR.1(2) structure. Structure-activity relationships reveal that para-carboxylate substitution on the hydrophilic ring and dihalogen substitution on the hydrophobic ring afford the most active TTR amyloid inhibitors.