预约演示

更新于：2026-07-19

Amisulpride

氨磺必利

更新于：2026-07-19

概要

基本信息

药物类型

小分子化药

别名

4-Amino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl)-2-methoxybenzamide、4-Amino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl)-O-anisamide、Aminosultopride

+ [20]

靶点

D2 receptor x D3 receptor

作用方式

拮抗剂

作用机制

D2 receptor拮抗剂(多巴胺D2受体拮抗剂)、D3 receptor拮抗剂(多巴胺D3受体拮抗剂)

治疗领域

神经系统疾病其他疾病

在研适应症

术后恶心呕吐精神分裂症急性精神分裂症+ [4]

非在研适应症

躁郁症1型终末期肾脏病躁狂+ [1]

原研机构

Acacia Research Corp.

在研机构

华益泰康药业股份有限公司Sanofi-Aventis Australia Pty Ltd.北京普德康利医药科技发展有限公司

+ [6]

非在研机构

Sanofi

南京正科医药股份有限公司

贵州景峰注射剂有限公司

+ [2]

权益机构

Eagle Pharmaceuticals, Inc.Acacia Pharma Group Ltd.

Laboratoire X.O

最高研发阶段批准上市

首次获批日期

澳大利亚 (2002-02-01),

急性精神分裂症慢性精神分裂症

最高研发阶段(中国)批准上市

特殊审评-

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结构/序列

分子式C17H27N3O4S

InChIKeyNTJOBXMMWNYJFB-UHFFFAOYSA-N

CAS号71675-85-9

关联

119

项与氨磺必利相关的临床试验

NCT07631910

/ Not yet recruitingN/AIIT

Transcutaneous Electrical Acupoint Stimulation Versus Sham Stimulation Combined With Dexamethasone Versus Amisulpride for Preventing Postoperative Nausea and Vomiting After Laparoscopic Gynecological Surgery: A Randomized Controlled Factorial Trial

1. Background Postoperative nausea and vomiting (PONV) is a common complication after general anesthesia, with an incidence as high as 80% in gynecological laparoscopic surgery. Transcutaneous electrical acupoint stimulation (TEAS) has shown potential as a non-invasive, side-effect-free intervention. Combining pharmacological agents (dexamethasone or amisulpride) with TEAS may provide a synergistic preventive effect, aligning with enhanced recovery after surgery (ERAS) principles.
2. Study Objectives To evaluate the preventive effect of TEAS on PONV in patients undergoing gynecological laparoscopic surgery, compared with sham stimulation.
To explore the synergistic effect of dexamethasone or amisulpride when combined with TEAS, and to optimize PONV prevention strategies.
To assess the impact of multimodal intervention on postoperative recovery quality, length of hospital stay, and patient satisfaction.
To evaluate the safety of the combined interventions and record any adverse events.
3. Study Design Design type: 2×2 factorial, randomized, double-blind (participants, outcome assessors, and data analysts blinded to group assignment).
Randomization: 1:1:1:1 allocation using an online randomization tool.
3.1 Study Groups Group Intervention A TEAS + Dexamethasone B TEAS + Amisulpride C Sham stimulation + Dexamethasone D Sham stimulation + Amisulpride 3.2 Participants Inclusion criteria: Age 18-65 years; ASA physical status I-II; scheduled for elective gynecological laparoscopic surgery (e.g., ovarian cystectomy, myomectomy) under general anesthesia; willing to provide informed consent.
Exclusion criteria: Severe cardiac, hepatic, renal, or pulmonary disease; allergy or skin disease at TEAS application site; Receipt of antiemetics within 24 h before surgery; Implanted cardiac pacemaker, cardioverter-;pregnancy or lactation; vulnerable populations (e.g., critically ill, psychiatric disorders, cognitive impairment, illiteracy); any condition deemed unsuitable by the investigator.
3.3 Interventions A wearable transcutaneous electrical acupoint stimulation (TEAS) wristband will be applied to the P6 (Neiguan) acupoint on the dominant upper extremity. The P6 acupoint is located approximately 3-5 cm proximal to the distal wrist crease, between the tendons of the flexor carpi radialis and palmaris longus. The device integrates the stimulating electrodes within the wristband and does not require external adhesive electrodes.
TEAS or sham stimulation will be administered at three time points: 30 minutes before surgery and 24 and 48 hours after surgery, with each session lasting 30 minutes.
Dexamethasone 5 mg (off-label for PONV; approved for inflammatory/allergic conditions).
Amisulpride 5 mg.
3.4 Outcome Measures
Primary outcomes (0-48 h postoperatively):
PONV incidence (proportion of patients with nausea, vomiting, or retching). PONV severity (0 = none, 1 = nausea only, 2 = vomiting/retching, 3 = refractory nausea/vomiting).
Secondary outcomes:
Recovery quality: time to first flatus, first ambulation, hospital stay, bowel function recovery.
Patient satisfaction: Visual Analogue Scale (VAS, 0-10) and QoR-15 score (0-150).
Rescue antiemetic use. Management needs for severe PONV. Postoperative pain (VAS at rest and on movement) and opioid consumption. Device-related adverse events (skin irritation, burning, allergy). Drug-related adverse events (e.g., hyperglycemia, hypotension, headache, dizziness, QT prolongation).
Intraoperative hemodynamics and postoperative complications (e.g., infection, shivering, urinary retention).
3.5 Follow-up Schedule Postoperative day 1 (24 h): PONV assessment, time to first flatus and ambulation.
Postoperative day 2 (48 h): PONV incidence/severity, rescue medication. At discharge: Satisfaction, hospital stay (via in-person or telephone follow-up).
4. Sample Size Calculation Assumptions: PONV incidence 50% in control groups, 30% in TEAS groups; two-sided α = 0.05; power = 80%.
Each main effect level requires
93 patients. For a 2×2 factorial design with 1:1:1:1 allocation, this translates to 47 patients per group (total 188). Accounting for a 10% dropout rate, final sample size = 212 patients (53 per group).
5. Data Management and Confidentiality Electronic Data Capture (EDC) system with unique coding (no direct identifiers).
Access restricted to authorized research team members.
6. Informed Consent Written informed consent will be obtained from each participant after full explanation of the study purpose, procedures, risks, and benefits. Participants are informed of their right to withdraw at any time.
7. Adverse Event Management Dexamethasone-related AEs (transient hyperglycemia, blood pressure fluctuation, gastrointestinal discomfort, rare allergic reactions).
Amisulpride-related AEs (headache, dizziness, constipation/diarrhea, QT prolongation, allergic reactions).
TEA-related AEs (local skin discomfort, redness, itching, rare blisters or mild burns).

开始日期2026-07-01

申办/合作机构

浙江大学医学院附属邵逸夫医院（浙江省邵逸夫医院）

ChiCTR2600124217

/ Not yet recruiting临床4期IIT

The efficacy and safety of paliperidone palmitate injection(II) as a replacement for oral medication in the treatment of schizophrenia

开始日期2026-04-25

申办/合作机构-

NCT07348172

/ Not yet recruiting早期临床1期IIT

Characterizing Drug Liking During Drug Administration in Peri-procedural Clinical Settings

The purpose of this study is to evaluate whether medications used in peri-procedural clinical settings can modulate drug liking.

开始日期2026-03-01

申办/合作机构

Stanford University

100 项与氨磺必利相关的临床结果

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100 项与氨磺必利相关的转化医学

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100 项与氨磺必利相关的专利（医药）

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1,935

项与氨磺必利相关的文献（医药）

2026-07-01·JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY

Risperidone-Induced Priapism

Review

作者: Atodaria, Priya ; Garcia, Elpidio ; Appiah-Kubi, Edmund ; Owusu-Antwi, Philipa ; Muhialdain, Muhialdain ; Shah, Zainab ; Drits, Elina

Background::

Risperidone, a second-generation antipsychotic with strong alpha-1 adrenergic receptor affinity, has been associated with priapism, a rare but serious urological emergency. This adverse effect remains underrecognized in psychiatric settings. We synthesized published reports on risperidone-induced priapism, summarized clinical characteristics, and highlighted preventive and management strategies.

Methods::

A systematic literature search was conducted across PubMed, EMBASE, Scopus, Medline, PubMed Central, Google Scholar, PsyArXiv, and PsycINFO from 1957 to 2024 using combinations of “risperidone,” “risperdal,” and “priapism.” Eligible studies included those describing priapism following risperidone exposure. Non-human studies, reviews, editorials, and articles without full-text access were excluded. Reviewers independently screened articles and assessed their quality using the Joanna Briggs Institute appraisal tool; resolved discrepancies by a third investigator.

Results::

From 987 screened records, 58 studies were included. Priapism occurred across all age groups and at a wide range of doses. Episodes were reported during both treatment initiation and maintenance. Risk factors included sickle cell disease, G6PD deficiency, cocaine or alcohol use, and prior prolonged erection. Management involved conservative measures, aspiration, intracavernosal sympathomimetics, and surgical shunting. Rechallenge frequently resulted in recurrence, whereas switching to agents with lower alpha-1 affinity, such as olanzapine or amisulpride, was typically effective.

Conclusions::

Risperidone-induced priapism can occur irrespective of dose or treatment duration, causing serious complications if unrecognized. This review highlights the importance of comprehensive evaluation before risperidone initiation, early identification, appropriate management, and clinician awareness of preventable adverse effects.

2026-06-02·INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY

Three-week effect of amisulpride, aripiprazole, and olanzapine on gene expression in peripheral blood in individuals with schizophrenia spectrum disorders

Article

作者: Torsvik, Anja ; Klæbo Reitan, Solveig M ; Steen, Vidar M ; Trentani, Andrea ; Skrede, Silje ; Stokowy, Tomasz K ; Joa, Inge ; Johnsen, Erik ; Rettenbacher, Maria ; Kroken, Rune A

Abstract:

Objective:

Antipsychotic drugs are to varying degrees associated with hematological side-effects and peripheral metabolic and immunological changes. Here, we aimed to characterize the initial transcriptional changes in peripheral leukocytes from individuals with schizophrenia spectrum disorder (SSD) after starting antipsychotic treatment with amisulpride, aripiprazole, or olanzapine.

Methods:

We analyzed RNA sequencing data obtained from peripheral whole blood samples from 100 individuals with SSD (41 antipsychotic-naïve [AP-naïve], 10 AP-free, and 49 AP-switching at inclusion) collected at baseline and after 1 and 3 weeks of antipsychotic drug use. Data from 36 healthy controls (HC) collected at baseline and after 3 weeks without any intervention were included. We analyzed age- and sex-adjusted differentially expressed genes between SSD and HC before and after treatment and stratified by previous antipsychotic use. A linear mixed model was applied to study longitudinal gene expression changes associated with the antipsychotic drug that was used.

Results:

After 3 weeks of antipsychotic use, the AP-switching group had the most significant transcriptional changes, characterized by increased expression of genes typically transcribed by immature erythroid cells and immature neutrophil cells. This gene profile showed no correlation with symptoms score. Interestingly, the immature neutrophil-associated gene signature was more pronounced in participants receiving olanzapine, and partly also amisulpride, but not aripiprazole. In contrast, only minor transcriptional changes were observed in the AP-naïve participants.

Conclusions:

These findings suggest that prior antipsychotic exposure may have a priming effect on leukocyte gene expression, which results in a transcriptional response indicative of stress erythropoiesis and neutropoiesis when switching to a new antipsychotic drug. This response appears to be independent of psychosis symptom severity.

2026-06-01·COMPREHENSIVE PSYCHIATRY

Real-world effectiveness of antipsychotic polytherapy on rehospitalization in psychotic disorders: A French nationwide cohort analysis

Article

作者: Bournane, Riad ; Cals-Maurette, Mallory ; Panes, Arnaud ; Schmidt, Aurélie ; Falissard, Bruno ; Nuss, Philippe ; Baloche, Emmanuelle ; Llorca, Pierre-Michel

BACKGROUND:

Antipsychotic polytherapy (APP) is common in clinical practice for psychotic disorders. Previous studies suggest that APP may offer advantages over monotherapy (APM) regarding effectiveness and all-cause discontinuation. This nationwide study assessed the reproducibility and robustness of these findings. The primary objective was to compare psychiatric readmission rates between APP and APM in psychotic disorder patients METHODS: Data were extracted from the French National Health insurance database (SNDS). Patients aged 18 or older with at least one psychiatric hospitalization between 1 January 2014 and 31 December 2020 were included. The primary outcome was time to psychiatric readmission. A within-individual study design was applied to limit confounding, by comparing periods with different treatment exposures within the same patient FINDINGS: A total of 234,959 adults with at least one hospitalization for a psychotic condition were included, with a median follow-up of 7 years. Antipsychotic treatment was associated with a (20%-50%) reduction in psychiatric readmission risk compared with no treatment. Rehospitalization remained common (71.6%). The median cumulative rehospitalization duration was 67 days, and 21.8% of patients had more than four admissions. Among the 71.1% exposed to APP, several combinations demonstrated distinct benefits. Clozapine-inclusive combinations (with risperidone or amisulpride) and loxapine-amisulpride combinations reduced rehospitalization risk. Quetiapine combinations also lowered risk by (10%- 20%) compared with quetiapine monotherapy INTERPRETATION: Derived from a large cohort, our findings corroborate previous evidence that APP's benefit reduces psychiatric rehospitalization and support its utility for psychotic specific patient subpopulations. This study confirms the reproducibility and robustness of APP's effectiveness in real-world settings.

270

项与氨磺必利相关的新闻（医药）

2026-07-13

·BioSpace

LB Pharmaceuticals Reports Inducement Grant to New Employee Under Nasdaq Listing Rule 5635(c)(4) - July 10, 2026

NEW YORK, July 10, 2026 (GLOBE NEWSWIRE) -- LB Pharmaceuticals Inc (“LB Pharmaceuticals” or the “Company”) (Nasdaq: LBRX), today announced that it has granted to Christopher Zergebel, the new Senior Vice President, Clinical Operations of LB Pharmaceuticals, an equity award outside of, but subject to the terms and conditions of, the LB Pharmaceuticals Inc 2025 Equity Incentive Plan. The equity award was granted on July 10, 2026, pursuant to the “inducement grant” exception provided under Nasdaq Listing Rule 5635(c)(4) as an inducement material to Mr. Zergebel entering into employment with LB Pharmaceuticals. Mr. Zergebel received an option to purchase 75,000 shares of LB Pharmaceuticals’ common stock, respectively. The option carries a ten-year term and an exercise price per share equal to $32.95, which was the closing price of LB Pharmaceuticals’ common stock on the date of grant, and vests over 4 years, with 25% of the shares underlying the options vesting on the first anniversary of the grant date and an additional 1/48 th of the shares vesting monthly thereafter, subject to continuous service through the applicable vesting dates. About LB-102 LB-102 is a novel, once-daily, orally administered investigational small molecule and potential first benzamide antipsychotic in the United States for the treatment of neuropsychiatric disorders. A methylated derivative of amisulpride, a widely used antipsychotic outside the United States, LB-102 was developed to retain amisulpride’s benefits while addressing its limitations. LB-102 is a potent and selective antagonist of D2, D3, and 5HT-7 receptors with few off-target effects and broad therapeutic potential across psychosis and mood disorders. In early 2025, LB Pharmaceuticals announced positive data from a four-week placebo-controlled, double-blinded, Phase 2 trial in patients with acute schizophrenia. In this trial, LB-102 demonstrated statistically significant benefit versus placebo at all doses studied, including rapid onset of effect at week 1 and sustained benefit through the endpoint of the trial, a potentially class-leading safety pro low rates of EPS (including akathisia), minimal sedation and few GI side effects, alongside effects on negative symptoms and cognitive performance. These data underscore LB-102’s potential to address multiple dimensions of neuropsychiatric illness. The pivotal Phase 3 NOVA-2 trial of LB-102 for acute schizophrenia and the Phase 2 ILLUMINATE-1 trial of LB-102 for bipolar 1 depression have been initiated, and a Phase 2 trial of LB-102 in adjunctive treatment of MDD is planned. Additional expansion opportunities for LB-102 include predominantly negative symptoms of schizophrenia, Alzheimer’s disease psychosis and agitation, as well as other neuropsychiatric diseases. About LB Pharmaceuticals LB Pharmaceuticals is a late-stage biopharmaceutical company developing novel therapies for the treatment of schizophrenia, bipolar depression, adjunctive treatment of major depressive disorder and other neuropsychiatric diseases. The Company is building a pipeline that leverages the broad therapeutic potential of its lead product candidate, LB-102, which the Company believes has the opportunity to be the first benzamide antipsychotic drug approved for neuropsychiatric disorders in the United States. LB-102, if approved, has the potential to become a mainstay of psychiatric practice by offering a balanced clinical activity and tolerability pro provides a potentially attractive alternative to branded and generic therapeutics for the treatment of a broad range of neuropsychiatric diseases. Media and Investor Contact Ellen Rose erose@lbpharma.us

临床2期临床结果临床3期

2026-07-07

·精准药物

JMC："老靶点"不服老！近十五年超1/3 FDA新药竟来自这些"常青树"

点击蓝字 ↑ 关注药学观澜近日，合肥工业大学谢周令/中国药科大学李志裕在药物化学权威期刊Journal of Medicinal Chemistry上发表了一篇题为"既往成药治疗靶点的演进策略：典范案例中的药物化学启示"的综述论文，系统梳理了2010—2025年间FDA批准的小分子药物中，那些"老树发新芽"的既往成药靶点如何通过药物化学创新实现持续产出，并提炼出可推广至未来药物设计的三大核心策略。该综述首先通过大数据分析指出，在2010—2025年FDA批准的460余个小分子药物中，约35.8%的靶点为2010年前即已成药的"legacy靶点"，其中GPCR（34.8%）和激酶（7.2%）占比显著，且CNS疾病（62.1%）和感染性疾病（50.0%）领域尤为依赖这类靶点。文章随后以GABA_A受体、DRD2/5-HT_2A受体、青霉素结合蛋白（PBPs）、细菌DNA旋转酶/拓扑异构酶IV、雄激素受体（AR）及Bcr-Abl六大代表性靶点为范例，深入剖析了"靶点再活化"（target revitalization）的三种药物化学路径：（1）基于成药药物的优化（drug-from-drug optimization），如瑞马唑仑的软药设计、头孢洛扎的膜通透性改造；（2）新机制驱动的药物优化，包括变构调节、信号偏向性调控、共价抑制、双靶/多靶策略及靶向蛋白降解（PROTAC）等；（3）新适应症的拓展，如氟班色林从抗抑郁药 repositioning 为HSDD治疗药物、吡马万色林作为5-HT_2A反向激动剂获批帕金森病精神病适应症。作者特别强调，这些"常青"靶点的持续成功并非源于简单的PK优化或"me-too"式改良，而是依赖于机制层面的根本性创新——例如神经甾体结合位点的挖掘使GABA_A受体超越了苯二氮䓬的局限性，DFG-out结合模式使Bcr-Abl抑制剂攻克了T315I gatekeeper突变，而DBO类β-内酰胺酶抑制剂则通过"非自杀底物"机制重新激活了PBP靶向抗生素的临床价值。综述最后展望，随着变构调控、偏向性信号、诱导邻近技术（PROTAC/RIPTAC）等策略的成熟，既往成药靶点仍将在差异化、耐药弹性及临床可及性方面展现巨大潜力，为药物化学家提供"低风险、高回报"的理性设计空间。 Introduction 治疗药物靶点是疾病病理生理中可调控以产生治疗获益的核心生物分子，蛋白质靶点（GPCRs、激酶、离子通道、核受体等）是研究最广泛、成药最成功的类别。截至2025年，已识别超3700个靶点，但仅约560个获FDA批准，瓶颈显著。2010—2025年间，460余个小分子药物对应193个靶点，GPCRs（22.3%）和激酶（20.2%）占比最高，治疗领域集中于癌症、CNS和感染性疾病。其中69个为2010年前已成药的"legacy靶点"，GPCRs占34.8%而激酶仅7.2%，且CNS领域legacy靶点占比达62.1%，远高于肿瘤的17.5%，表明肿瘤药物发现侧重新靶点，而CNS和抗感染领域仍高度依赖既往成功靶点。近年来，药物化学研究日益超越增量式改进，转向变构调节、信号偏向性、共价抑制和靶向蛋白降解等新机制，以解决耐药性、安全性、选择性及疗效等长期挑战，并利用这些靶点参与多生理过程的特性拓展适应症。本综述以GABA_A受体、DRD2、PBPs和AR等代表性靶点为例，分析其再活化策略，提炼可推广的药物化学设计洞见，为未来药物发现提供参考。 Results ①GABA_A受体 GABA_A受体是CNS中研究最广泛的抑制性神经递质受体，由19种亚基组成五聚体配体门控离子通道，不同亚型介导不同生理功能——α1关联镇静抗惊厥，α2/3介导抗焦虑，α5参与认知记忆。经典苯二氮䓬类作为完全激动剂存在耐受、依赖及镇静运动障碍等不良反应，且缺乏亚型选择性。部分激动策略通过"天花板效应"降低不良反应风险，代表药物包括2023年中国获批的地咪西泮和2011年FDA获批的氯巴占，后者对α2亚基亲和力更高，镇静副作用更低。α2/3亚型选择性调节剂因苯二氮䓬口袋高度同源而难以实现，基于效能偏向的MRK-409虽在临床前实现抗焦虑无镇静，但人体试验失败，凸显物种间功能"设定点"差异及动物模型预测局限。α5选择性因结构差异相对可行，但basmisanil和S44819均因临床转化困难终止开发。靶向神经甾体结合位点成为成功替代策略：该位点位于跨膜结构域，可调控突触外δ亚基受体，拓宽治疗谱。brexanolone（2019年，产后抑郁，静脉）、ganaxolone（2022年，癫痫，口服）和zuranolone（2023年，重度抑郁/产后抑郁，口服）三代神经甾体类药物通过逐步优化PK性质实现临床成功。双靶策略如stiripentol（GABA_A受体+CYP450，2018年）和cenobamate（GABA_A受体+电压门控钠通道，2019年）以及软药设计（remimazolam，2020年）和丙泊酚衍生优化（ciprofol，2020年）则分别从多靶点协同和成药性改善角度延伸了GABA_A靶点的治疗价值。 ②多巴胺D2受体/5-羟色胺2A受体 DRD2和5-HT2AR是CNS药物发现中经典的互补靶点对，双靶调节可改善阴性症状并减少锥体外系副作用，但代谢综合征等不良反应仍未解决。2010年以来获批的lurasidone、cariprazine和brexpiprazole均保留LCAP骨架——质子化哌嗪与保守Asp的离子键是GPCR正构口袋的结构约束。三者的临床差异化源于耐受性改善而非阳性症状控制：lurasidone兼具5-HT7R拮抗活性但PK受限；cariprazine优先部分激动DRD3，改善阴性症状和认知，正进行MDD III期试验；brexpiprazole降低DRD2内在活性、增强5-HT2AR拮抗，减少静坐不能。三者均保留5-HT1AR部分激动活性，提示重新平衡多靶点信号而非最大化单靶调控是降低不良反应的关键。lumateperone（2019年）以四环喹喔啉新骨架实现突触前DRD2部分激动/突触后DRD2-5-HT2AR拮抗，兼SERT抑制和间接NMDA调控，为目前耐受性最佳的代表。5-HT2AR拮抗并非抗精神病疗效的绝对必要条件：IHCH7041（临床前）作为DRD2/3-5-HT1AR部分激动剂、5-HT2AR无亲和力，挑战了长期范式；pimavanserin（2016年）作为5-HT2AR反向激动剂获批帕金森病精神病，验证了无DRD2活性的选择性调控策略。lumateperone-5-HT2AR晶体结构揭示的延伸口袋和β-arrestin偏向信号，催生了低致幻风险的偏向性激动剂（如化合物21）。信号偏向策略亦推广至其他靶点，如2023年获批的G蛋白偏向μOR激动剂oliceridine。此外，双价配体（化合物23）、变构调节剂（SB-269652）等临床前策略，以及药物重定位（amisulpride用于术后恶心呕吐、flibanserine用于HSDD）和前药优化（aripiprazole lauroxil长效注射剂）进一步拓展了该靶点对的成药空间。 ③青霉素结合蛋白 PBPs是1960年代确立的β-内酰胺类靶点，其转肽酶（TP）结构域催化细胞壁交联，按分子量分为HMM（PBP1-3，含双功能Class A和单功能Class B）和LMM（PBP4-6）两类，后者参与维持细胞形态和抗生素耐受。不同菌种间PBPs数量和功能分类差异显著，增加了靶向复杂性。临床β-内酰胺均通过共价酰化TP结构域发挥作用，但缺乏亚型选择性且不抑制转糖基酶（TG）结构域。细菌耐药三大机制为：低亲和力耐药PBPs（如MRSA的PBP2a）、β-内酰胺酶水解、以及革兰阴性菌外膜通透性降低。增强耐药PBP亲和力是核心再工程策略：ceftaroline fosamil（2010年，首个五代头孢）通过先结合PBP2a变构位点触发构象重排、再协同占据催化位点的独特机制规避MRSA耐药；ceftobiprole medocaril（2024年，第二个五代头孢）则通过乙烯基吡咯烷酮占据PBP2a深疏水隧道直接暴露催化Ser403，无需两步激活。非β-内酰胺类选择性PBP4抑制剂9314848可避免酶水解，拓展了化学型空间。增强外膜通透性和酶稳定性方面，ceftolozane（2014年）的碱性氨基脲侧链减少外排识别并增强AmpC稳定性；cefiderocol（2019年）以氯儿茶酚铁螯合策略利用细菌铁摄取通路跨膜，规避孔蛋白丢失耐药且对丝氨酸/金属β-内酰胺酶均稳定；sulopenem etzadroxil（2024年）为首个口服青霉烯前药。DBO类β-内酰胺酶抑制剂（avibactam、relebactam、durlobactam等）以可逆共价加合、非"自杀底物"机制重新激活配对抗生素；zidebactam和nacubactam更兼具直接PBP2抑制活性，展示DBO作为非β-内酰胺PBP抑制剂新类别的潜力；vaborbactam（2017年）则以硼酸骨架实现高亲和慢解离。 ④细菌DNA旋转酶/拓扑异构酶IV 细菌DNA旋转酶和Topo IV为高度同源但功能分化的II型拓扑异构酶，分别调控DNA复制和染色体分离，均由切割连接亚基（GyrA/ParC）和ATP结合亚基（GyrB/ParE）组成。喹诺酮类靶向GyrA/ParC，但QRDR突变（如GyrA Ser83/Asp87破坏Mg²⁺配位桥）和类相关毒性限制其应用。药物优化策略改善了喹诺酮的PK和耐药谱：finafloxacin（2014年）以C-8氰基降低pKa保持酸性环境膜通透性；delafloxacin（2017年）以3-羟基氮杂环丁烷实现酸性条件下非两性离子态增强穿透；ozenoxacin（2017年）去除C-6氟消除光毒性，三者均降低外排敏感性。非喹诺酮类新机制抑制剂是克服QRDR耐药的核心策略：化合物45保留ParC结合但增强ParE相互作用并绕过QRDR；gepotidacin（2025年，NBTI类）以LHS-RHS三药效团双 engagement GyrA二聚体界面和DNA，与喹诺酮机制根本不同；zoliflodacin（2025年）以螺嘧啶三酮骨架主要结合GyrB而非GyrA，诱导致死双链断裂，为近20年首个单纯性淋病新疗法。此外，针对氨基糖苷乙酰转移酶修饰和Qnr靶点保护等耐药机制的新型抑制剂开发亦日益受到重视。 ⑤雄激素受体 AR为1960年代鉴定的类固醇激素受体，ADT阻断其信号是前列腺癌经典疗法。AR含NTD、DBD、铰链区和LBD四个功能域，迄今所有获批拮抗剂均靶向LBD激素结合口袋。第一代氟他胺（1989年）受肝毒性和突变致激动限制；第二代恩扎卢胺（2012年）和阿帕鲁胺（2018年）以硫代乙内酰脲骨架克服部分早期突变，但F876L及LBD缺失仍导致耐药，且存在CNS毒性。PK优化可降低中枢暴露：SHR3680（2022年）引入二羟基减少BBB穿透。改变结合机制是克服突变耐药的关键：达罗鲁胺（2019年）以柔性吡唑骨架替代刚性硫代乙内酰脲，在F876L突变时仍维持拮抗构象；普克鲁胺以噁唑疏水尾强化H12置换并可能促进AR降解，但III期终止。非LBD策略应对AR-V7等剪接变体：EPI-7386（I/II期）靶向NTD，ASC-J9（临床前）破坏AR-共调节因子相互作用促降解。PROTAC可克服多重耐药：ARV-766（II期）和BMS-986365（III期，2025年）为口服AR降解剂。RIPTACs如HLD-0915（I/II期）通过肿瘤特异性蛋白-泛必需蛋白三元复合物选择性杀伤癌细胞。非肿瘤适应症拓展方面，clascoterone（2020年，痤疮）和pyrilutamide（雄激素性脱发III期）靶向皮肤局部AR；proxalutamide曾进入COVID-19 III期试验；enobosarm（AR激动剂）虽肿瘤适应症终止，但提示肌肉萎缩等非肿瘤潜力。 ⑥Bcr-Abl Bcr-Abl为9号和22号染色体易位产生的酪氨酸激酶，与CML和Ph+ ALL相关。2001年伊马替尼获批标志CML治疗突破，但ATP位点突变导致耐药。博舒替尼（2012年）对F317L等突变广谱有效，但对T315I gatekeeper突变无效。普纳替尼（2012年）以乙炔连接子规避T315I位阻、稳定DFG-out构象，但脱靶VEGFR致心血管毒性；奥雷巴替尼（2021年，中国）以吡唑并吡啶骨架增强铰链氢键，覆盖更复杂突变；PF-114则通过优化铰链结合基团提高选择性、降低心血管风险。变构抑制是根本性耐药解决方案：阿西米尼（2021年）靶向豆蔻酰口袋稳定失活态，规避ATP位点突变交叉耐药，适用于普纳替尼耐药的T315I经治患者；瑞巴替尼以switch-control机制锁定失活构象，但临床开发未成功。非ATP竞争性策略仍面临变构口袋突变和代偿通路耐药。PROTAC如SIAIS178因PK和选择性挑战进展缓慢；共价抑制剂化合物71以赖氨酸靶向策略实现持续抑制。此外，普纳替尼等多靶点活性（FGFR、PDGFR、RET、KIT）提示双靶/多靶策略可拓展Bcr-Abl至其他适应症。 Discussion 尽管"既往成药治疗靶点"一词可能暗示过时，但GABA_A受体、DRD2等靶点因其在疾病驱动生物学中的核心作用，近年来仍是小分子药物发现与开发的中心。针对这类靶点的药物发现利用已确立的药理学知识，相比全新靶点具有更高的成功概率和更低的商业风险，因此持续吸引工业界和学术界关注；尤其在感染性疾病等领域，新靶点的识别和验证仍具挑战，进一步推动了既往成药靶点的研究。2010—2025年间，2010年前即已成药的靶点占所有成功靶点的35.8%，在CNS和感染性疾病治疗中占比尤为突出。本综述系统分析了GABA_A受体、DRD2/5-HT2AR、PBPs、细菌旋转酶/Topo IV、AR和Bcr-Abl等代表性靶点跨越CNS、感染性疾病和肿瘤领域的开发策略，Table 1进一步总结了其他既往成药靶点2010—2025年的开发轨迹，凸显了这些"常青"靶点的持久转化价值。值得注意的是，成功再活化这类靶点更少依赖增量式PK优化，更多依赖作用机制创新。主要药物化学设计策略可归纳为三类：一是基于成药药物的优化，强调成药性改善——不同患者亚群在起效速度、给药途径、组织分布、给药频率和安全性方面需求各异，理性优化PK和理化性质而非仅靶点亲和力可显著提升临床价值，代表策略包括前药设计（aripiprazole lauroxil）、软药设计（remimazolam）、组织选择性重工程（SHR3680）和骨架跃迁（peramivir），在感染领域则通过增强外膜通透性（cefiderocol）或减少外排泵敏感性（finafloxacin）克服耐药。二是新机制驱动的药物优化——部分激动剂/拮抗剂、变构调节剂、信号偏向性配体、共价抑制剂、双靶/多靶抑制剂和靶向蛋白降解剂等机制差异化治疗策略，主要通过减轻脱靶副作用和克服耐药机制来再活化先前被认为饱和或难治的靶点，如变构Bcr-Abl抑制剂阿西米尼规避ATP位点耐药、G蛋白偏向性μOR激动剂oliceridine显著降低传统阿片类药物不良反应、共价抑制剂dacomitinib通过不可逆相互作用增强突变EGFR效价、PROTAC（ARV-766）和双靶/多靶抑制剂（regorafenib）提供抑制适应性耐药通路的新机制途径，以及更精确的多靶策略（lumateperone）最小化不良反应改善整体安全性耐受性；在抗感染领域，利用新结合模式作用于耐药靶点变体（ceftaroline、avibactam、gepotidacin）是恢复或增强抗耐药病原体活性的代表性策略。三是新适应症拓展——为成药靶点扩展临床适应症是再活化的有力策略，除药物重定位（amisulpride）外，开发具有新机制或增强选择性新化学实体尤为有效，如5-HT2AR拮抗剂传统用于精神分裂症，但机制差异化的反向激动剂pimavanserin获批帕金森病精神病、双靶5-HT1A/5-HT2A调节剂flibanserin获批HSDD；高选择性ROCK2抑制剂belumosudil获批慢性移植物抗宿主病（此前非选择性ROCK1/2抑制剂未能有效覆盖）；选择性I类HDAC抑制剂givinostat（2024年）获批杜氏肌营养不良，与早期主要面向肿瘤的vorinostat等HDAC靶向药物形成显著差异。文献详细全面信息请跳转原文阅读： https://doi.org/10.1021/acs.jmedchem.6c00858 说明欢迎合理转载，请写明来源于【药学观澜】，公众号以个人学习和分享最新科研成果为目的，本文内容为阅读文献提炼总结的内容，因学识有限，难免有所疏漏和谬误，恳请批评指正。标记【原创】指原创编译，是出于便于传播目的，著作权归出版社与作者所有。分享让更多人看看

2026-07-01

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热门口溶膜，同日两家企业获批！

7月1日，NMPA发布大批批准件，布瑞哌唑口溶膜同日两家企业获批，这款口溶膜属于改良制剂，获批极其顺利。布瑞哌唑口溶膜已有齐鲁和科伦两家企业顺利获批。这两家企业同时拥有片剂、口崩片和口溶膜，致力于全方面掌握剂型。上海欣峰和博志研新则只做了口溶膜，专一于口溶膜领域。同一日，石药欧意的布瑞哌唑片也顺利过评。布瑞哌唑这一成分算是彻底卷起来了，截至目前布瑞哌唑片共有15家企业过评，加上原研大冢制药，竞争已达16家。布瑞哌唑口崩片共有4家企业过评，原研未上市。布瑞哌唑口溶膜共4家企业获批，改良上市，无原研。原研大冢制药距今上市不过两年，从布瑞哌唑片首家过评到现在也才不到7个月，此品种甚至还没进医保。布瑞哌唑，这一成分确实是很优秀。由大冢制药和丹麦灵北制药联合研发，专为治疗精神分裂症而设计，其临床优势体现在精准的受体作用机制、低副作用风险、广泛的适应症覆盖以及经济可及性等方面，尤其适合需要长期治疗且对副作用敏感的患者群体。目前临床常用的抗精神病药物主要分三代：第一代抗精神病药物也就是传统的抗精神病药物。常见的药物包括氟哌啶醇、五氟利多和氯丙嗪、奋乃静等。这一类药物长期服用可能会导致催乳素水平增高，而且会影响女性月经，导致月经失调等。第二代抗精神病药也称为非典型抗精神病药，疗效更优、不良反应更少。包括氯氮平、阿立哌唑、利培酮、苯海索、伊潘立酮、鲁拉西酮、氨磺必利、舒必利等，副作用相对较小。第三代抗精神病药物化拮抗为部分激动，进一步减少不良反应，包括阿立哌唑、卡利拉嗪和布瑞哌唑。布瑞哌唑属于第三代，疗效好、不良反应更小，产品过硬，与此同时布瑞哌唑的核心专利在2026年4月就会到期，因此这个品种相当抢手。布瑞哌唑2023年合计销售额在20亿美元左右，稳坐“十亿美元俱乐部”宝座。 ↓⭐关注药通社，洞见行业趋势↓

100 项与氨磺必利相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D07310	氨磺必利	N05AL05	DB06288

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
术后恶心呕吐	美国	LXO Ireland DAC	2020-02-26
精神分裂症	中国	Sanofi-Aventis Groupe SA	2004-06-04
急性精神分裂症	澳大利亚	Sanofi-Aventis Australia Pty Ltd.	2002-02-01
慢性精神分裂症	澳大利亚	Sanofi-Aventis Australia Pty Ltd.	2002-02-01

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
恶心和呕吐	临床3期	中国	贵州景峰注射剂有限公司	2023-01-12
恶心和呕吐	临床3期	中国	北京普德康利医药科技发展有限公司	2023-01-12
恶心	临床3期	法国	Acacia Pharma Group Ltd.	2013-07-01
恶心	临床3期	德国	Acacia Pharma Group Ltd.	2013-07-01
呕吐	临床3期	法国	Acacia Pharma Group Ltd.	2013-07-01
呕吐	临床3期	德国	Acacia Pharma Group Ltd.	2013-07-01
化疗引起的恶心和呕吐	临床2期	丹麦	Acacia Pharma Group Ltd.	2011-02-01
化疗引起的恶心和呕吐	临床2期	英国	Acacia Pharma Group Ltd.	2011-02-01
躁郁症1型	临床2期	捷克	Sanofi	2004-05-01
躁郁症1型	临床2期	法国	Sanofi	2004-05-01

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01029769 (CTgov)	N/A	分裂情感性障碍 \| 精神分裂症	350	amisulpride+Olanzapine (Early Non-responders Switched)	繭範遞鏇糧繭觸製築築 = 網憲糧醖襯構鹽構觸製構夢鹹遞範願餘製廠糧 (餘範齋簾簾醖鏇鑰觸鏇, 鬱襯蓋鏇鹽觸積鹹鑰築 ~ 選壓鹽鑰壓醖衊餘選糧) 更多	-	2024-10-21
				amisulpride+Olanzapine (Ealy Non-responders Non-switched)	網衊窪積願餘範蓋範鬱(製網壓鏇鹽艱衊齋築糧) = 蓋構廠淵糧築選顧齋淵範顧鹽積醖鏇範夢窪齋 (膚廠選鑰艱齋遞鏇鑰願, 15.1)
NCT04876521 (PSD-AOFC, CTgov)	临床4期	-	60	Amisulpride (Amisulpride Group)	壓憲鹽襯壓簾選艱顧衊(廠窪憲襯淵積鏇遞遞糧) = 願鬱艱膚襯襯窪淵鏇鹽範鑰顧構積廠選膚齋齋 (繭醖鹹憲壓憲鹽艱鏇網, 0.47) 更多	-	2024-09-19
				Olanzapine-Fluoxetine Combination (Olanzapine-Fluoxetine Group)	壓憲鹽襯壓簾選艱顧衊(廠窪憲襯淵積鏇遞遞糧) = 簾憲觸範網餘鑰繭糧網範鑰顧構積廠選膚齋齋 (繭醖鹹憲壓憲鹽艱鏇網, 0.60) 更多
Pubmed 人工标引	N/A	精神分裂症	25	olanzapine+Amisulpride	顧窪構製鹽鏇糧獵構積(鏇積範齋齋壓艱鏇網壓) = not statistically significant 鹽遞鬱襯顧夢淵鹽鏇夢 (蓋膚壓範繭齋糧鹽顧齋 ) 更多	积极	2022-08-31
				olanzapine
Phase III trial of IV amisulpride (ASCO2022)	临床3期	术后恶心呕吐	465	Amisulpride 10 mg	襯遞艱選構積襯糧壓廠(襯獵窪衊鬱醖廠鬱鑰鹹) = 鏇淵構夢製襯夢夢鑰窪鏇糧顧廠衊製願繭築蓋 (齋齋鑰鏇鏇餘醖夢鹽鏇 ) 更多	积极	2022-06-02
				Placebo	襯遞艱選構積襯糧壓廠(襯獵窪衊鬱醖廠鬱鑰鹹) = 構鬱觸鑰網願壓鏇餘遞鏇糧顧廠衊製願繭築蓋 (齋齋鑰鏇鏇餘醖夢鹽鏇 ) 更多
NCT01248195 (OPTiMiSE study, Pubmed \| Schizophr Res)	临床4期	精神障碍	-	Amisulpride	選憲壓鹽夢製夢鹽願願(糧夢積醖鬱鹽觸窪膚鏇): HR = 2.865 (95% CI, 1.187 ~ 6.916), P-Value = 0.019	-	2021-05-01
				Olanzapine
NCT03583489 (Pubmed \| Anesth Analg)	临床1期	术后恶心呕吐	30	Amisulpride 10 mg	襯繭鏇顧壓鏇壓蓋醖衊(膚餘醖範淵糧觸醖夢蓋) = 觸衊選遞鬱繭構淵齋襯襯鹽夢網獵製繭構廠顧 (襯齋遞製壓糧築醖顧壓, 3.53 ~ 6.96)	积极	2019-12-09
				Amisulpride 10 mg + Ondansetron 4 mg	襯繭鏇顧壓鏇壓蓋醖衊(膚餘醖範淵糧觸醖夢蓋) = 艱艱顧淵鹽範齋鹽憲窪襯鹽夢網獵製繭構廠顧 (襯齋遞製壓糧築醖顧壓, 55.48 ~ 9.16)
NCT01991821 (CTgov)	临床3期	恶心 \| 术后恶心呕吐 \| 呕吐	368	APD421 (APD421)	鹽壓餘願襯醖觸衊壓積 = 壓鹹範壓夢觸廠願壓齋鑰衊遞壓蓋遞醖淵選觸 (壓餘選遞繭遞窪齋壓築, 膚艱遞憲衊衊繭鏇獵製 ~ 衊鏇鑰鹽廠選鹽艱壓選) 更多	-	2019-08-02
				Placebo (Placebo)	鹽壓餘願襯醖觸衊壓積 = 鹹廠鏇艱鑰壓襯構餘鹹鑰衊遞壓蓋遞醖淵選觸 (壓餘選遞繭遞窪齋壓築, 顧積廠壓齋廠艱構餘範 ~ 夢鹹製鏇淵廠糧遞選觸) 更多
NCT01857232 (Pubmed \| Support Care Cancer)	临床2期	恶心和呕吐	342	Amisulpride 10mg	選餘齋觸鹽鏇願選範醖(糧憲遞壓範窪糧廠構憲) = 夢廠繭鏇鹽觸鏇鑰糧繭窪鏇壓網鹽襯蓋艱餘構 (獵蓋齋鏇顧網構築願積 )	积极	2019-07-01
				Placebo	選餘齋觸鹽鏇願選範醖(糧憲遞壓範窪糧廠構憲) = 衊遞積衊繭壓遞鑰積範窪鏇壓網鹽襯蓋艱餘構 (獵蓋齋鏇顧網構築願積 )
NCT02449291 (Pubmed \| Anesth Analg)	临床3期	术后恶心呕吐	568	Placebo	鏇膚鹽鏇簾齋簾壓餘鑰(積構淵範餘淵壓範鹽夢) = 齋艱衊鏇壓構夢夢鏇鬱憲鏇醖窪衊憲鑰齋鏇蓋 (艱壓願艱遞壓範積選範 )	积极	2019-06-01
				Amisulpride 5 mg	鏇膚鹽鏇簾齋簾壓餘鑰(積構淵範餘淵壓範鹽夢) = 襯壓廠構製鏇廠蓋鏇簾憲鏇醖窪衊憲鑰齋鏇蓋 (艱壓願艱遞壓範積選範 )
NCT01857232 (CTgov)	临床2期	恶心 \| 呕吐	342	Dexamethasone+Ondansetron+Fosaprepitant (Control)	鑰鑰衊膚網醖範簾觸蓋 = 襯遞衊鹽遞膚衊鑰蓋廠遞遞遞願淵廠窪鏇選簾 (鑰膚範網夢獵壓鬱遞築, 齋蓋積簾壓襯艱餘鹽鬱 ~ 網齋遞鹹鬱觸製繭鬱鑰) 更多	-	2019-03-12
				APD403 IV+Placebo+Ondansetron (PLACEBO)	鑰鑰衊膚網醖範簾觸蓋 = 積製鏇鑰壓窪醖鑰襯獵遞遞遞願淵廠窪鏇選簾 (鑰膚範網夢獵壓鬱遞築, 鬱襯齋鏇鬱鏇製夢衊鏇 ~ 衊齋糧簾遞廠鑰顧顧網)