Cabergoline

吲哚是一种芳香杂环分子，具有一个苯环和一个含氮吡咯环组成的双环结构。 吲哚中的氮原子提供一对孤对电子，形成共轭体系，从而稳定了吲哚结构。 这对孤电子使吲哚化合物呈现弱碱性(pKa=16.2和pK,=17.6)。 由于吡咯环的电子密度相对较高以及氮原子的共轭效应，吲哚可以在其吡咯环的3位发生亲电取代反应(图la)。 图 1 (a) 全球有超过70种含有吲哚的合成药物在市场上销售，并被证明具有良好的医疗效果(图1b)。用于治疗的疾病包括糖尿病、癌症、白血病、丙型肝炎、心理障碍和其他临床问题。自2015年起，美国(FDA)专门批准了14种含吲哚药物，其中3种是在2021年批准的(图2)。 二氢麦角胺(DHE,1)的化学结构中含有吲哚支架，对头颅血管平滑肌中的5-HT1b受体具有激动活性，治疗偏头痛。 昂丹司琼(2)是一种血清素5-HT3受体拮抗剂，用于预防癌症治疗期间和手术后的恶心和呕吐(图3a)。 图 3 (a) 双氢麦角胺（1）和昂丹司琼（2）的结构。(b) 双氢麦角胺(1)与其靶点（左）和昂丹司琼(2)与其靶点（右）的关键靶点相互作用。 替加色罗(3)在临床相关水平上被认为是5-HT(4)受体的激动剂和5-HT(2B)受体的拮抗剂，其作用之一是使受损的胃肠道运动恢复正常。 多拉司琼(4)用于中度致吐的癌症化疗以及术后恶心和呕吐的治疗(图5)。它是一种高效、选择性的血清素5-HT3受体拮抗剂。 Tropisetron（5）可抑制5HT3受体上血清素的活性，从而抑制放疗和化疗引起的呕吐。 Vilazodone(6)是5HT-1A受体的部分激动剂，专门抑制中枢神经系统对血清素的再摄取。 在治疗偏头痛急性发作方面，三苯氧胺药物(5-羟色胺受体激动剂)比其他药物更有效、更耐受。这类药物具有起效快、用药时间长、不良反应少等优点。Sumatriptan(7),zolmitriptan(8),naratriptan(9), rizatriptan(10), almotriptan (11), frovatriptan (12), eletriptan (13), 和 oxitriptan (14) 是国外已商业化的曲坦类药物的代表。(图7)。 环氧化酶(COX)被称为前列腺素G/H合成酶，而吲哚美辛是一种非特异性的可逆性环氧化酶抑制剂。吲哚美辛(18)属于吲哚-3-乙酸类，其官能团包括对氯苯甲酰基、甲基和甲氧基。它是一种非甾体抗炎药(NSAID), 具有消炎、镇痛和解热的特点(图11a)。 Acemetacin(19)是另一种强效非甾体抗炎药物，由吲哚-3-乙酸衍生而来(图12)。它主要通过酯分解代谢为吲哚美辛。 Etodolac(20)是一种非甾体抗炎药，具有消炎、镇痛和解热作用(图13a)。以前被认为是一种非选择性COX抑制剂，但现在被认为对COX-2的选择性是COX-1的5-50倍。 Carprofen(21)是兽医用作缓解老年犬关节炎症状的辅助疗法的一种非甾体抗炎药，人们认为卡洛芬(21)的作用机制是抑制环氧化酶的活性。 帕金森病的药物 Cabergoline(22)是一种长效多巴胺受体激动剂，与D2受体有很强的亲和力，用于治疗高催乳素血症和帕金森综合症(图14a)。 Lisuride(23)可能是某些血清素受体的激动剂,也可能是多巴胺D1受体的拮抗剂。可降低催乳素水平，适量服用可阻止偏头痛，从药理上讲，(23)是还是一种帕金森氏症药物。 治疗子宫脱垂的药物 甲基麦角新碱(26)是一种麦角生物碱，临床上用于预防和治疗产后和流产后出血(图17)。这种药物与多巴胺D1受体结合，作为一种拮抗剂发挥作用，可增强平滑肌的张力、节奏和节律性收缩的幅度。 治疗精神疾病的药物 sertindole（27）是一种抗精神分裂症药物，也是一种苯基吲哚衍生物。临床试验证实，(27)对低水平的多巴胺D2占位具有疗效。 治疗神经系统疾病的药物 吲哚洛尔(28)是一种非选择性β肾上腺素受体拮抗剂，用于治疗心房颤动、水肿、高血压和室性心动过速。 卡维地洛(29)通过阻断β肾上腺素受体防止运动引起的心动过速， 它对α-1肾上腺素能受体的作用可使血管平滑肌放松，从而降低外周血管阻力和血压。 尼麦角林(30)是一种半合成麦角衍生物，可用于治疗认知功能障碍。这种药剂作为一种选择性α-1A肾上腺素能受体抑制剂用于临床(图20)。 治疗生殖系统疾病的药物 麦角新碱(32)是一种麦角生物碱，可用于控制妇女的产后和流产后出血。 结构与活性关系明确的药物 Tezacaftor(41)属于用于治疗囊性纤维化(CFTR)增效剂。美国食品及药物管理局批准该药与ivacaftor联合用于治疗囊性纤维化(图28a)。该药物可在2至4小时内达到血浆浓度峰值。 2015年2月23日，FDA批准口服去乙酰化酶(DAC)抑制剂Panobinostat(42)用于治疗多发性骨髓瘤(图29a)。(42)在体外与人体血浆蛋白的结合率约为90%,这与其浓度无关。其吲哚环可以通过与Asn645的氢键相互作用为SAR创造一个稳定的框架(图29b)。 结构与活性关系不完全明确的药物 Metergoline(52)是一种麦角衍生物，用于治疗女性高催乳素闭经症(图39)。通过靶向钠通道而非5HT受体来抑制钠通道的活性，从而导致泌乳素分泌减少。 Lurbinectedin(53)是一种抗癌天然产物。该药物在化疗中用于治疗转移性小细胞肺癌。Lurbinectedin(53)在临床试验中的治疗反应率和持续时间在2020年获得了加速批准。 总体而言，在FDA批准的药物中，含有吲哚环的药物数量在不断增加。在药物分子中引入吲哚砌块也已成为药物化学和药物设计中的一种常见策略。现有的含吲哚药物因其特殊的结构，在抗癌、抗炎和抗病毒等方面具有显著的临床价值。 参考文献：DOI: 10.1039/d3md00677h 内容来源于网络，如有侵权，请联系删除。

-- New clinical data accepted for oral and e-Poster presentation at AACE -- -- e-ECE clinical data previously presented at Endocrine Society’s 2021 annual meeting -- NEEDHAM, Mass., May 20, 2021 (GLOBE NEWSWIRE) -- Chiasma, Inc. (NASDAQ: CHMA), (“Chiasma” or the “Company”), a commercial-stage biopharmaceutical company utilizing its delivery platform technology to develop and commercialize oral therapies to improve the lives of patients with rare diseases currently treated with burdensome and painful injections, today announced that it will virtually present encore data from its MPOWERED™ Phase 3 clinical trial at the 23rd European Congress of Endocrinology (e-ECE) (May 22-26, 2021) and new data from the MPOWERED trial at the 30th Annual American Association of Clinical Endocrinology (AACE) Meeting (May 26-29, 2021). Oral presentations and posters for display are summarized below: e-ECE 2021 Oral PresentationTitle: A Phase 3 Large International Noninferiority Trial (MPOWERED): Assessing Maintenance of Response to Oral Octreotide Capsules in Comparison to Injectable Somatostatin Receptor LigandsPresenter: Maria Fleseriu, M.D., FACE, Professor, Medicine and Neurological Surgery, Director OHSU Northwest Pituitary CenterSession Date/Time: Wednesday, May 26, 2021, 8:30 a.m. – 9:30 a.m. EDT e-ECE 2021 e-Poster PresentationsTitle: Safety Results from MPOWERED, a Phase 3 Trial of Oral Octreotide Capsules in Adults with AcromegalyPresenter: Pamela Freda, M.D., Columbia University Session Date/Time: Monday, May 24, 2021, 8:00 a.m. – 8:30 a.m. EDT Title: Oral Octreotide Capsules Lowered Incidence and Improved Severity of Acromegaly Symptoms Compared to Injectable Somatostatin Receptor Ligands—Results from the MPOWERED TrialPresenter: Nienke Biermasz, M.D., Ph.D., Leiden University Medical Center Session Date/Time: Tuesday, May 25, 2021, 8:00 a.m. – 8:30 a.m. EDT Title: Addition of Cabergoline to Oral Octreotide Capsules May Improve Biochemical Control in Patients with Acromegaly Who Are Inadequately Controlled with MonotherapyPresenter: Maria Fleseriu, M.D., FACE, Professor, Medicine and Neurological Surgery, Director OHSU Northwest Pituitary CenterSession Date/Time: Tuesday, May 25, 2021, 8:00 a.m. – 8:30 a.m. EDT Title: Improved Acromegaly Patient Satisfaction with Oral Octreotide Capsules Compared with Injectable Somatostatin Receptor Ligands in the MPOWERED TrialPresenter: Murray B. Gordon, M.D., Allegheny General HospitalSession Date/Time: Wednesday, May 26, 2021, 8:00 a.m. – 8:30 a.m. EDT AACE 2021 Oral PresentationTitle: Improved Quality of Life and Work Productivity in Patients with Acromegaly Receiving Oral Octreotide Capsules in the Phase 3 MPOWERED TrialPresenter: Nienke Biermasz, M.D., Ph.D., Leiden University Medical CenterSession Date/Time: Thursday, May 27, 2021, 1:30 p.m. – 1:45 p.m. EDT AACE 2021 Late-Breaker e-Posters - Available online via the virtual e-Poster Gallery beginning May 26Title: Effects of Prior Injectable Somatostatin Receptor Ligand Type and Dose in Patients with Acromegaly Receiving Oral Octreotide Capsules in the Phase 3 MPOWERED TrialLead Author: Murray B. Gordon, M.D., Allegheny General Hospital Title: Injection Site Reactions and Their Impact in Patients with Acromegaly Receiving Injectable Somatostatin Receptor Ligands in the Phase 3 MPOWERED TrialLead Author: Murray B. Gordon, M.D., Allegheny General Hospital To register and view the full schedules as well as abstracts, visit e-ECE’s website here and AACE’s website here. Chiasma will sponsor a product theatre presentation at the AACE annual meeting titled “Understanding the Management of Acromegaly with MYCAPSSA® (octreotide) Delayed-Release Oral Capsules” on Wednesday, May 26 at 2:45 p.m. EDT. Anthony P. Heaney, M.D., Ph.D., Professor, UCLA, will lead the presentation and a live Q&A session. About the MPOWERED™ Trial The MPOWERED trial was a global, non-inferiority, randomized, open-label and active-controlled, 15-month trial intended to support approval of MYCAPSSA in the European Union. Chiasma completed enrollment of 146 adult acromegaly patients into the trial in June 2019, of which 92 patients were deemed responders to octreotide capsules per the protocol following a six-month run-in were randomized to either octreotide capsules (n=55) or injectable somatostatin receptor ligands (octreotide LAR or lanreotide autogel) (n=37), and then followed for an additional nine months. The trial was designed to evaluate the proportion of patients who maintain their biochemical response to octreotide capsules and patient-reported outcomes in patients treated with octreotide capsules, compared to patients treated with leading injectable somatostatin analogs. About MYCAPSSA INDICATION AND IMPORTANT SAFETY INFORMATION INDICATION AND USAGE MYCAPSSA (octreotide) delayed-release capsules, for oral use, is a somatostatin analog indicated for long-term maintenance treatment in acromegaly patients who have responded to and tolerated treatment with octreotide or lanreotide. CONTRAINDICATIONS Hypersensitivity to octreotide or any of the components of MYCAPSSA. Anaphylactoid reactions, including anaphylactic shock, have been reported in patients receiving octreotide. IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS MYCAPSSA can cause problems with the gallbladder. Monitor patients periodically. Discontinue if complications of cholelithiasis are suspected. Blood sugar, thyroid levels, and vitamin B12 levels should be monitored and treated accordingly. Bradycardia, arrhythmia, or conduction abnormalities may occur. Treatment with drugs that have bradycardia effects may need to be adjusted. ADVERSE REACTIONS The most common adverse reactions (incidence >10%) are nausea, diarrhea, headache, arthralgia, asthenia, hyperhidrosis, peripheral swelling, blood glucose increased, vomiting, abdominal discomfort, dyspepsia, sinusitis, and osteoarthritis. DRUG INTERACTIONS The following drugs require monitoring and possible dose adjustment when used with MYCAPSSA: cyclosporine, insulin, antidiabetic drugs, calcium channel blockers, beta blockers, lisinopril, digoxin, bromocriptine, and drugs mainly metabolized by CYP3A4. Counsel women to use an alternative non-hormonal method of contraception or a back-up method when MYCAPSSA is used with combined oral contraceptives. Patients taking proton pump inhibitors, H2-receptor antagonists, or antacids concomitantly with MYCAPSSA may require increased dosages of MYCAPSSA. PREGNANCY Advise premenopausal females of the potential for an unintended pregnancy. To report SUSPECTED ADVERSE REACTIONS, contact the product information department at 1-844-312-2462 or FDA at 1-800-FDA-1088 or  The full Prescribing Information for MYCAPSSA is available at . About Acromegaly Acromegaly typically develops when a benign tumor of the pituitary gland produces too much growth hormone, ultimately leading to significant health problems. Common features of acromegaly are facial changes, intense headaches, joint pain, impaired vision and enlargement of the hands, feet, tongue and internal organs. Serious health conditions associated with the progression of acromegaly include type 2 diabetes, hypertension, respiratory disorders and cardiac and cerebrovascular disease. Chiasma estimates that approximately 8,000 adult acromegaly patients are chronically treated with somatostatin analog injections in the United States. About Chiasma Chiasma is a commercial-stage biopharmaceutical company focused on developing and commercializing oral therapies to improve the lives of patients who face challenges associated with their existing treatments for rare and serious chronic diseases. Employing its Transient Permeability Enhancer (TPE®) technology platform, Chiasma seeks to develop oral medications that are currently available only as injections. In June 2020, Chiasma received FDA approval of MYCAPSSA for long-term maintenance therapy in acromegaly patients who have responded to and tolerated treatment with octreotide or lanreotide. MYCAPSSA, the first and only oral somatostatin analog approved by the FDA, is available for commercial sale. Chiasma is headquartered in Needham, MA with a wholly owned subsidiary in Israel. MYCAPSSA, TPE and CHIASMA are registered trademarks of Chiasma. For more information, please visit the company’s website at . Forward-Looking Statements This release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding the data from the MPOWERED trial and the therapeutic potential of MYCAPSSA. Such statements are subject to numerous important factors, risks and uncertainties, many of which are beyond the company’s control, that may cause actual events or results to differ materially from the company’s current expectations. Management’s expectations and, therefore, any forward-looking statements in this press release could be affected by risks and uncertainties. For a discussion of these and other risks and uncertainties, and other important factors, any of which could cause the company’s actual results to differ from those contained in the forward-looking statements, see the section entitled “Risk Factors” in Chiasma’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2021, and in subsequent filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and Chiasma undertakes no duty to update this information unless required by law. Investor Relations and Corporate Communications:Ashley RobinsonLifeSci Advisors, LLC617-430-7577arr@lifesciadvisors.com Media Relations:Patrick BurseyLifeSci Communications646-876-4932pbursey@lifescicomms.com