Agitation and psychosis are key behavioral and psychological symptoms of Alzheimer's disease (AD). For family and caregivers of patients, such symptoms are critical factors of distress and increased burden, but medication to treat them is limited. In most cases, drugs for other neuropsychiatric diseases have been used to manage these symptoms in an off-label manner. Due to the complex pathological background of AD and limited clinical data, obtaining proof of concept for the treatment of these symptoms is challenging. However, in 2023, the U.S. Food and Drug Administration approved brexpiprazole as the first and only drug to treat agitation in AD. Several other compounds have been evaluated in clinical situations. This review highlights recent pipelines being developed for agitation and psychosis for patients living with AD.
躁动和精神病是阿尔茨海默病(AD)的主要行为和心理症状。对于患者家属和护理人员来说,这些症状是造成痛苦和增加负担的关键因素,但治疗这些症状的药物却很有限。在大多数情况下,治疗其他神经精神疾病的药物在标签外被用于控制这些症状。由于注意力缺失症的病理背景复杂,临床数据有限,要获得治疗这些症状的概念证明具有挑战性。不过,2023 年,美国食品和药物管理局批准了布来匹唑(brexpiprazole),这是首个也是唯一一个治疗 AD 躁动的药物。其他几种化合物也已进行了临床评估。本综述重点介绍了近期正在开发的治疗AD患者激动和精神病的新药。
{"title":"Clinical Pipelines for Alzheimer's Disease Psychosis and Agitation.","authors":"Takuya Oguma, Kohei Jino","doi":"10.1248/cpb.c23-00416","DOIUrl":"https://doi.org/10.1248/cpb.c23-00416","url":null,"abstract":"<p><p>Agitation and psychosis are key behavioral and psychological symptoms of Alzheimer's disease (AD). For family and caregivers of patients, such symptoms are critical factors of distress and increased burden, but medication to treat them is limited. In most cases, drugs for other neuropsychiatric diseases have been used to manage these symptoms in an off-label manner. Due to the complex pathological background of AD and limited clinical data, obtaining proof of concept for the treatment of these symptoms is challenging. However, in 2023, the U.S. Food and Drug Administration approved brexpiprazole as the first and only drug to treat agitation in AD. Several other compounds have been evaluated in clinical situations. This review highlights recent pipelines being developed for agitation and psychosis for patients living with AD.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sunflower seed extract, an antioxidant agent registered on the List of Existing Food Additives in Japan, was evaluated using HPLC, and three common constituents were detected. These peaks were identified as monocaffeoylquinic acids (3-O-caffeoylquinic acid, 4-O-caffeoylquinic acid, and 5-O-caffeoylquinic acid [chlorogenic acid]). Upon scrutinizing other components, dicaffeoylquinic acids (isochlorogenic acids; 3,4-di-O-caffeoylquinic, 3,5-di-O-caffeoylquinic, and 4,5-di-O-caffeoylquinic acids) were also identified. Structures of two newly isolated compounds were determined to be 3-O-(3S-2-oxo-3-hydroxy-indole-3-acetyl)-5-O-caffeoylquinic and 4-O-(3S-2-oxo-3-hydroxy-indole-3-acetyl)-5-O-caffeoylquinic acids. To identify the components that contribute to the antioxidant activity of sunflower seed extract, we fractionated the food additive sample solution and examined the active fractions for 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity. Monocaffeoylquinic and dicaffeoylquinic acids showed high DPPH activity, including their contribution to the antioxidant activity of this food additive. DPPH radical scavenging activity of the new compounds showed almost the same value as that of the positive control, Trolox. Therefore, the contribution of these compounds was also considered.
{"title":"Chromatographic Evaluation and Characterization of Constituents of Sunflower Seed Extract Used as Food Additives.","authors":"Yoshiaki Amakura, Takashi Uchikura, Morio Yoshimura, Naoko Masumoto, Yuzo Nishizaki, Naoki Sugimoto","doi":"10.1248/cpb.c23-00670","DOIUrl":"10.1248/cpb.c23-00670","url":null,"abstract":"<p><p>Sunflower seed extract, an antioxidant agent registered on the List of Existing Food Additives in Japan, was evaluated using HPLC, and three common constituents were detected. These peaks were identified as monocaffeoylquinic acids (3-O-caffeoylquinic acid, 4-O-caffeoylquinic acid, and 5-O-caffeoylquinic acid [chlorogenic acid]). Upon scrutinizing other components, dicaffeoylquinic acids (isochlorogenic acids; 3,4-di-O-caffeoylquinic, 3,5-di-O-caffeoylquinic, and 4,5-di-O-caffeoylquinic acids) were also identified. Structures of two newly isolated compounds were determined to be 3-O-(3S-2-oxo-3-hydroxy-indole-3-acetyl)-5-O-caffeoylquinic and 4-O-(3S-2-oxo-3-hydroxy-indole-3-acetyl)-5-O-caffeoylquinic acids. To identify the components that contribute to the antioxidant activity of sunflower seed extract, we fractionated the food additive sample solution and examined the active fractions for 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity. Monocaffeoylquinic and dicaffeoylquinic acids showed high DPPH activity, including their contribution to the antioxidant activity of this food additive. DPPH radical scavenging activity of the new compounds showed almost the same value as that of the positive control, Trolox. Therefore, the contribution of these compounds was also considered.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139484995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This study showcases the 1,2-migration reactions of alkyl and aryl groups on the indole molecule. Trifluoromethanesulfonic acid effectively facilitates the migration of the substituent from C3- to C2-position of the indole structure. The resulting C2-substituted indoles offer a valuable pathway for the synthesis of natural products and medicinal compounds.
{"title":"Synthesis of 2-Substituted Indoles via Migration Reaction of 3-Substituted Indoles with Triflic Acid.","authors":"Kosuke Nakashima, Yuka Kudo, Yasuyuki Matsushima, Shin-Ichi Hirashima, Tsuyoshi Miura","doi":"10.1248/cpb.c23-00792","DOIUrl":"10.1248/cpb.c23-00792","url":null,"abstract":"<p><p>This study showcases the 1,2-migration reactions of alkyl and aryl groups on the indole molecule. Trifluoromethanesulfonic acid effectively facilitates the migration of the substituent from C3- to C2-position of the indole structure. The resulting C2-substituted indoles offer a valuable pathway for the synthesis of natural products and medicinal compounds.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140206351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In clinical diagnosis, magnetic polystyrene nanoparticles (MPS NPs) are commonly applied to, e.g., the chemiluminescent immunoassay (CLEIA). However, the conventional preparation method of MPS NPs requires a long duration of heating to form polymer particles, which is inefficient. In this study, we prepared MPS NPs by emulsion solvent-evaporation without heating. We evaluated the effect of the solvent in the water and organic phases on the magnetic particle content. MPS NPs prepared by 4% (v/v) MeOH aqueous solution and adding stearic acid (SA) (4MeSA-MPS NPs) exhibited the highest magnetic particle content. Furthermore, CLEIA analysis indicates that the C-reactive protein detection limit is 80 pg/mL. Thus, 4MeSA-MPS NPs are promising for clinical diagnoses.
{"title":"Magnetic Polystyrene Nanoparticles Prepared by Emulsion Solvent-Evaporation for the Chemiluminescent Immunoassay.","authors":"Hiroaki Ichimaru, Masashi Kurimoto, Shigetoshi Kikuchi","doi":"10.1248/cpb.c23-00864","DOIUrl":"10.1248/cpb.c23-00864","url":null,"abstract":"<p><p>In clinical diagnosis, magnetic polystyrene nanoparticles (MPS NPs) are commonly applied to, e.g., the chemiluminescent immunoassay (CLEIA). However, the conventional preparation method of MPS NPs requires a long duration of heating to form polymer particles, which is inefficient. In this study, we prepared MPS NPs by emulsion solvent-evaporation without heating. We evaluated the effect of the solvent in the water and organic phases on the magnetic particle content. MPS NPs prepared by 4% (v/v) MeOH aqueous solution and adding stearic acid (SA) (4MeSA-MPS NPs) exhibited the highest magnetic particle content. Furthermore, CLEIA analysis indicates that the C-reactive protein detection limit is 80 pg/mL. Thus, 4MeSA-MPS NPs are promising for clinical diagnoses.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140305050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The triboelectric properties of active pharmaceutical ingredients (APIs) contribute to problems during the manufacturing of pharmaceuticals. However, the triboelectric properties of APIs have not been comprehensively characterized. In this study, the effect of salt formulation on the triboelectric properties of APIs was investigated. The triboelectric properties of three groups of amines, namely tertiary amines, purine bases, and amino acids, and their hydrochlorides were evaluated using a suction-type Faraday cage meter. Most of the hydrochloride salts exhibited more negative charges than the corresponding free bases, and the degree by which the triboelectric property changed upon hydrochlorination depended on the structural groups of the compounds. In the case of tertiary amines, the change in the zero-charge margin upon hydrochlorination was negatively correlated with the zero-charge margin of the free base. In contrast, hydrochlorination of the amino acids led to a significant change in the zero-charge margin. In most cases, salt formation also affected the triboelectric properties of API powders. Controlling the triboelectric properties of APIs solves various problems caused by the electrification of raw material powders and granules during the production of pharmaceuticals, thereby increasing the quality of produced pharmaceuticals.
{"title":"Triboelectrification of Active Pharmaceutical Ingredients: Amines and Their Hydrochloride Salts.","authors":"Kenta Fujinuma, Shota Okada, Kyu Hayashi, Masataka Ito, Hironori Suzuki, Kiyohiko Sugano, Shuji Noguchi","doi":"10.1248/cpb.c24-00303","DOIUrl":"10.1248/cpb.c24-00303","url":null,"abstract":"<p><p>The triboelectric properties of active pharmaceutical ingredients (APIs) contribute to problems during the manufacturing of pharmaceuticals. However, the triboelectric properties of APIs have not been comprehensively characterized. In this study, the effect of salt formulation on the triboelectric properties of APIs was investigated. The triboelectric properties of three groups of amines, namely tertiary amines, purine bases, and amino acids, and their hydrochlorides were evaluated using a suction-type Faraday cage meter. Most of the hydrochloride salts exhibited more negative charges than the corresponding free bases, and the degree by which the triboelectric property changed upon hydrochlorination depended on the structural groups of the compounds. In the case of tertiary amines, the change in the zero-charge margin upon hydrochlorination was negatively correlated with the zero-charge margin of the free base. In contrast, hydrochlorination of the amino acids led to a significant change in the zero-charge margin. In most cases, salt formation also affected the triboelectric properties of API powders. Controlling the triboelectric properties of APIs solves various problems caused by the electrification of raw material powders and granules during the production of pharmaceuticals, thereby increasing the quality of produced pharmaceuticals.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Although opioid analgesics are indispensable in treating pain, these drugs are accompanied by life-threatening side effects. While clinically relevant opioid drugs target the µ opioid receptor (MOR), a heterodimer between the MOR and the δ opioid receptor (DOR) has emerged as another target to develop safer analgesics. Although some heterodimer-preferring agonists have been reported so far, it is still difficult to activate the MOR/DOR heterodimer selectively in the presence of MOR or DOR monomers/homodimers. To gain insights to develop selective agonists for MOR/DOR, herein we prepared analogs of CYM51010, one of the reported heterodimer-preferring agonists, and collected structure-activity relationship information. We found that the ethoxycarbonyl group was needed for the activity for the heterodimer, although this group could be substituted with functional groups with similar sizes, such as an ethoxycarbonyl group. As for the acetylaminophenyl group, not a type of substituent, but rather a substituent located at a specific position (para-position) was essential for the activity. Changing the linker length between the acetylaminophenyl group and the piperidine moiety also had deleterious effects on the activity. On the other hand, the substitution of the acetylamino group with a trifluoroacetylamino group and the substitution of the phenethyl group with a benzyl group diminished the activities for the monomers/homodimers while keeping the activity for MOR/DOR, which enhanced the selectivity. Our findings herein will play an important role in developing selective agonists for MOR/DOR and for elucidating the physiological roles of this heterodimer in analgesic processes and in the establishment of side effects.
虽然阿片类镇痛药是治疗疼痛不可或缺的药物,但这些药物也伴随着危及生命的副作用。虽然临床上相关的阿片类药物以 µ 阿片受体(MOR)为靶点,但 MOR 和 δ 阿片受体(DOR)之间的异二聚体已成为开发更安全镇痛药的另一个靶点。虽然迄今已报道了一些异二聚体优先激动剂,但在存在 MOR 或 DOR 单体/同二聚体的情况下,仍难以选择性地激活 MOR/DOR 异二聚体。为了深入了解如何开发 MOR/DOR 的选择性激动剂,我们在本文中制备了 CYM51010 的类似物(已报道的异二聚体优先激动剂之一),并收集了结构-活性关系信息。我们发现,异二聚体的活性需要乙氧羰基,尽管该基团可以被类似大小的官能团(如乙氧羰基)取代。至于乙酰氨基苯基,其活性并非取决于取代基的类型,而是取决于位于特定位置(对位)的取代基。改变乙酰氨基苯基和哌啶之间的连接长度也会对活性产生不利影响。另一方面,用三氟乙酰氨基取代乙酰氨基和用苄基取代苯乙基会降低单体/同源二聚体的活性,而保持对 MOR/DOR 的活性,从而提高选择性。我们在本文中的发现将对开发 MOR/DOR 的选择性激动剂以及阐明这种异源二聚体在镇痛过程和副作用产生过程中的生理作用发挥重要作用。
{"title":"Structure-Activity Relationship Study of CYM51010, an agonist for the µ-δ Opioid Receptor Heterodimer.","authors":"Ayaka Watanabe, Shuma Yamada, Haruka Yoshida, Miku Inagaki, Nao Atsumi, Aoba Matsushima, Naoki Takahashi, Naoto Ishibashi, Takumi Ogino, Ryoto Someya, Ai Taguchi, Ryo Kagaya, Karin Ashizawa, Hinako Mendori, Yusuke Karasawa, Kaori Ohshima, Akinobu Yokoyama, Miki Nonaka, Kanako Miyano, Fumika Karaki, Shigeto Hirayama, Kennosuke Itoh, Yasuhito Uezono, Hideaki Fujii","doi":"10.1248/cpb.c24-00188","DOIUrl":"https://doi.org/10.1248/cpb.c24-00188","url":null,"abstract":"<p><p>Although opioid analgesics are indispensable in treating pain, these drugs are accompanied by life-threatening side effects. While clinically relevant opioid drugs target the µ opioid receptor (MOR), a heterodimer between the MOR and the δ opioid receptor (DOR) has emerged as another target to develop safer analgesics. Although some heterodimer-preferring agonists have been reported so far, it is still difficult to activate the MOR/DOR heterodimer selectively in the presence of MOR or DOR monomers/homodimers. To gain insights to develop selective agonists for MOR/DOR, herein we prepared analogs of CYM51010, one of the reported heterodimer-preferring agonists, and collected structure-activity relationship information. We found that the ethoxycarbonyl group was needed for the activity for the heterodimer, although this group could be substituted with functional groups with similar sizes, such as an ethoxycarbonyl group. As for the acetylaminophenyl group, not a type of substituent, but rather a substituent located at a specific position (para-position) was essential for the activity. Changing the linker length between the acetylaminophenyl group and the piperidine moiety also had deleterious effects on the activity. On the other hand, the substitution of the acetylamino group with a trifluoroacetylamino group and the substitution of the phenethyl group with a benzyl group diminished the activities for the monomers/homodimers while keeping the activity for MOR/DOR, which enhanced the selectivity. Our findings herein will play an important role in developing selective agonists for MOR/DOR and for elucidating the physiological roles of this heterodimer in analgesic processes and in the establishment of side effects.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Biosynthetic intermediates of siderophore vibrioferrin (VF), O-citryl-L-serine, 2-aminoethyl citrate, and alanine-2-amidoethyl citrate were respectively synthesized as a mixture of stereoisomers. These compounds were used as substrates for enzyme reactions using recombinant PvsA, PvsB, and PvsE proteins as corresponding enzyme equivalents. The results of our study show that each enzyme reacts with a respective substrate and produces VF along the proposed biosynthetic pathway. Furthermore, the results of this study will contribute to the understanding of VF biosynthetic enzymes and may help in the development of antimicrobial drugs by inhibiting siderophore biosynthetic enzymes.
{"title":"Synthesis of Biosynthetic Intermediates of Vibrioferrin and Enzyme Reactions Using Them as Substrates.","authors":"Hidemichi Mitome, Tomotaka Tanabe, Tatsuya Funahashi, Kazuki Akira","doi":"10.1248/cpb.c24-00168","DOIUrl":"https://doi.org/10.1248/cpb.c24-00168","url":null,"abstract":"<p><p>Biosynthetic intermediates of siderophore vibrioferrin (VF), O-citryl-L-serine, 2-aminoethyl citrate, and alanine-2-amidoethyl citrate were respectively synthesized as a mixture of stereoisomers. These compounds were used as substrates for enzyme reactions using recombinant PvsA, PvsB, and PvsE proteins as corresponding enzyme equivalents. The results of our study show that each enzyme reacts with a respective substrate and produces VF along the proposed biosynthetic pathway. Furthermore, the results of this study will contribute to the understanding of VF biosynthetic enzymes and may help in the development of antimicrobial drugs by inhibiting siderophore biosynthetic enzymes.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141330409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Henna is a plant-based dye obtained from the powdered leaf of the pigmented plant Lawsonia inermis, and has often been used for grey hair dyeing, treatment, and body painting. As a henna product, the leaves of Indigofera tinctoria and Cassia auriculata can be blended to produce different colour variations. Although allergy from henna products attributed to p-phenylenediamine, which is added to enhance the dye, is reported occasionally, raw material plants of henna products could also contribute to the allergy. In this study, we reported that raw material plants of commercial henna products distributed in Japan can be estimated by LC-high resolution MS (LC-HRMS) and multivariate analysis. Principal Component Analysis (PCA) score plot clearly separated 17 samples into three groups [I; henna, II; blended henna primarily comprising Indigofera tinctoria, III; Cassia auriculata]. This grouping was consistent with the ingredient lists of products except that one sample listed as henna was classified as Group III, indicating that its ingredient label may differ from the actual formulation. The ingredients characteristic to Groups I, II, and III by PCA were lawsone (1), indirubin (2), and rutin (3), respectively, which were reported to be contained in each plant as ingredients. Therefore, henna products can be considered to have been manufactured from these plants. This study is the first to estimate raw material plants used in commercial plant-based dye by LC-HRMS and multivariate analysis.
指甲花是一种植物染料,取自色素植物 Lawsonia inermis 的叶粉,常用于染白发、治疗和身体彩绘。作为指甲花产品,Indigofera tinctoria 和 Cassia auriculata 的叶子可以混合产生不同的颜色变化。虽然偶尔有报道称指甲花产品过敏是由于添加了对苯二胺来增强染料的效果,但指甲花产品的原料植物也可能导致过敏。在这项研究中,我们报告了通过液相色谱-高分辨质谱(LC-HRMS)和多元分析可以估算出在日本销售的商业指甲花产品的原料植物。主成分分析(PCA)得分图清楚地将 17 种样品分为三组[I;指甲花;II;主要由靛蓝组成的混合指甲花;III;决明子]。这种分组与产品的成分表一致,只有一个列为指甲花的样品被归为第 III 组,表明其成分标签可能与实际配方不同。根据 PCA,第 I 组、第 II 组和第 III 组的特征成分分别是律酮(1)、靛红素(2)和芦丁(3),据报告每种植物都含有这些成分。因此,可以认为指甲花产品是由这些植物制成的。本研究首次通过 LC-HRMS 和多元分析估算了用于商业植物染料的原料植物。
{"title":"Estimation for Raw Material Plants of a Henna Product Using LC-High Resolution MS and Multivariate Analysis.","authors":"Naohiro Oshima, Maiko Tahara, Tsuyoshi Kawakami, Akiko Yagami, Takumi Akiyama, Nahoko Uchiyama, Yoshiaki Ikarashi","doi":"10.1248/cpb.c24-00278","DOIUrl":"https://doi.org/10.1248/cpb.c24-00278","url":null,"abstract":"<p><p>Henna is a plant-based dye obtained from the powdered leaf of the pigmented plant Lawsonia inermis, and has often been used for grey hair dyeing, treatment, and body painting. As a henna product, the leaves of Indigofera tinctoria and Cassia auriculata can be blended to produce different colour variations. Although allergy from henna products attributed to p-phenylenediamine, which is added to enhance the dye, is reported occasionally, raw material plants of henna products could also contribute to the allergy. In this study, we reported that raw material plants of commercial henna products distributed in Japan can be estimated by LC-high resolution MS (LC-HRMS) and multivariate analysis. Principal Component Analysis (PCA) score plot clearly separated 17 samples into three groups [I; henna, II; blended henna primarily comprising Indigofera tinctoria, III; Cassia auriculata]. This grouping was consistent with the ingredient lists of products except that one sample listed as henna was classified as Group III, indicating that its ingredient label may differ from the actual formulation. The ingredients characteristic to Groups I, II, and III by PCA were lawsone (1), indirubin (2), and rutin (3), respectively, which were reported to be contained in each plant as ingredients. Therefore, henna products can be considered to have been manufactured from these plants. This study is the first to estimate raw material plants used in commercial plant-based dye by LC-HRMS and multivariate analysis.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141579057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alkene dipeptide isosteres (ADIs) are promising surrogates of peptide bonds that enhance the bioactive peptide resistance to enzymatic hydrolysis in medicinal chemistry. In this study, we investigated the substitution effects of an ADI on the energy barrier of cis-trans isomerization in the acetyl proline methyl ester (Ac-Pro-OMe) model. The (E)-alkene-type proline analog, which favors a cis-amide conformation, exhibits a lower rotational barrier than native Ac-Pro-OMe. A van't Hoff analysis suggests that the energy barrier is primarily reduced by enthalpic repulsion. It was concluded that although carbon-carbon double bonds and pyrrolidine rings individually increase the rigidity of the incorporation site, their combination can provide structural flexibility and disrupt bioactive conformations. This work provides new insights into ADI-based drug design.
烯二肽异构体(ADIs)是一种很有前景的肽键替代物,可增强生物活性肽在药物化学中抗酶水解的能力。在本研究中,我们研究了 ADI 对乙酰脯氨酸甲酯(Ac-Pro-OMe)模型中顺反异构化能障的取代效应。(E)-烯类脯氨酸类似物倾向于顺式酰胺构象,其旋转势垒低于原生 Ac-Pro-Ome。范特霍夫分析表明,能垒主要是通过焓斥力降低的。结论是,虽然碳碳双键和吡咯烷环单独使用会增加结合部位的刚性,但它们的组合可提供结构灵活性并破坏生物活性构象。这项研究为基于 ADI 的药物设计提供了新的见解。
{"title":"Substitution Effects of Alkene Dipeptide Isosteres on Adjacent Peptide Bond Rotation.","authors":"Chihiro Iio, Kohei Sato, Nobuyuki Mase, Tetsuo Narumi","doi":"10.1248/cpb.c24-00254","DOIUrl":"https://doi.org/10.1248/cpb.c24-00254","url":null,"abstract":"<p><p>Alkene dipeptide isosteres (ADIs) are promising surrogates of peptide bonds that enhance the bioactive peptide resistance to enzymatic hydrolysis in medicinal chemistry. In this study, we investigated the substitution effects of an ADI on the energy barrier of cis-trans isomerization in the acetyl proline methyl ester (Ac-Pro-OMe) model. The (E)-alkene-type proline analog, which favors a cis-amide conformation, exhibits a lower rotational barrier than native Ac-Pro-OMe. A van't Hoff analysis suggests that the energy barrier is primarily reduced by enthalpic repulsion. It was concluded that although carbon-carbon double bonds and pyrrolidine rings individually increase the rigidity of the incorporation site, their combination can provide structural flexibility and disrupt bioactive conformations. This work provides new insights into ADI-based drug design.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In order to introduce a cost-effective strategy method for commercial scale dry granulation at the early clinical stage of drug product development, we developed dry granulation process using formulation without API, fitted and optimized the process parameters adopted Design of Experiment (DOE). Then, the process parameters were confirmed using one formulation containing active pharmaceutical ingredient (API). The results showed that the roller pressure had significant effect on particle ratio (retained up to #60 mesh screen), bulk density and tapped density. The roller gap had significant influence on particle ratio and specific energy. The particle ratio was significantly affected by the mill speed (second level). The tabletability of the powder decreased after dry granulation. The effect of magnesium stearate on the tabletability was significant. In the process validation study, the properties of the prepared granules met the requirements for each response studied in the DOE. The prepared tablets showed higher tensile strength, good content uniformity of filled capsules, and the dissolution profiles of which were consistent with that of clinical products. This drug product process development and research strategies could be used as a preliminary experiment for the dry granulation process in the early clinical stage.
为了在药物产品开发的早期临床阶段为商业规模的干法制粒引入一种经济有效的策略方法,我们利用不含原料药的配方开发了干法制粒工艺,并采用实验设计(DOE)对工艺参数进行了拟合和优化。然后,使用一种含有活性药物成分(API)的制剂对工艺参数进行了确认。结果表明,辊筒压力对颗粒比率(保留至 #60 目筛网)、体积密度和攻丝密度有显著影响。滚筒间隙对颗粒比率和比能量有显著影响。碾磨速度(第二级)对颗粒比率有明显影响。干法制粒后,粉末的片剂性降低。硬脂酸镁对片剂性的影响很大。在工艺验证研究中,制备的颗粒的特性符合 DOE 研究中每个响应的要求。制备的片剂显示出较高的拉伸强度,填充胶囊的含量均匀性良好,其溶出曲线与临床产品一致。该药物产品工艺开发和研究策略可作为干法制粒工艺在早期临床阶段的初步实验。
{"title":"Systematic DOE Approach for Dry Granulation Study at Early Clinical Stage of Novel Drugs: An Industrial Case.","authors":"Weiqi Chen, Xiaolei Wang, Hengli Yuan, Qixuan Guan, Chun Wang, Zhiying Dong, Shicheng Zhang, Jianping Yao, Jinyang Shen","doi":"10.1248/cpb.c23-00801","DOIUrl":"https://doi.org/10.1248/cpb.c23-00801","url":null,"abstract":"<p><p>In order to introduce a cost-effective strategy method for commercial scale dry granulation at the early clinical stage of drug product development, we developed dry granulation process using formulation without API, fitted and optimized the process parameters adopted Design of Experiment (DOE). Then, the process parameters were confirmed using one formulation containing active pharmaceutical ingredient (API). The results showed that the roller pressure had significant effect on particle ratio (retained up to #60 mesh screen), bulk density and tapped density. The roller gap had significant influence on particle ratio and specific energy. The particle ratio was significantly affected by the mill speed (second level). The tabletability of the powder decreased after dry granulation. The effect of magnesium stearate on the tabletability was significant. In the process validation study, the properties of the prepared granules met the requirements for each response studied in the DOE. The prepared tablets showed higher tensile strength, good content uniformity of filled capsules, and the dissolution profiles of which were consistent with that of clinical products. This drug product process development and research strategies could be used as a preliminary experiment for the dry granulation process in the early clinical stage.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}