Design and development of biological response modifiers

生物反应调节剂的设计和开发

基本信息

批准号：
14103018
负责人：
HASHIMOTO Yuichi
金额：
$ 72.72万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (S)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-14103018/
关键词：
nuclear receptor structural development steroid hormone antagonists enzyme inhibitor molecular design bioprobe thalidomide 核内受容体リガンド Liver X Receptor (LXR)Farnesoid X Receptor (FXR)PPAR ステロイドビタミンD アンドロゲン FXR プロゲステロンプロ

项目摘要

Various biological response modifiers, including nuclear receptor ligands (agonists/antagonists) and enzyme inhibitors, were designed and prepared, aiming development of agents for the treatment of chronic diseases (cancers, diabetes, rheumatoid diseases etc). Methodologically, functional regulation hypothesis of nuclear receptors based on the lingand-dependent conformational change of their substructure, helix 12, and multi-template hypothesis have been proposed. Based on these hypotheses,(1)ligands (agonists and antagonists) of nuclear receptors [retinoic acid receptors (RARs), retinoid X receptors (RXRs), androgen receptor, progesterone receptor, estrogen receptor, peroxisome proliferators-activated receptors (PPARs), farnsoid X receptor (FXR), liver X receptors (LXRs), and viamine D receptor,(2)specfic and potent inhibitors of tumor necrosis factor (TNF)-α production, tubulin polymerization, puromycin-sensitive aminopeptidase (PSA), α-glucosidase, dipeptidylpeptidase (DPP) type IV, … More tumor cell invasion, histone deacetylase (HDAC), heparanase, calcineulin, cyclooxygenase (COX), nitrogen oxidase synthase (NOS), μ-calpain, thymidine phosphorylase, and angiogenesis, have been created.Typical compounds created in this research project includes;(a)a synthetic retinoid, Am80 (tamibarotene), which has been launched since 2005 as a medicament for the treatment of acute promyelocytic leukemia, and is now under phase II clinical trial for the treatment of Crohn's diseases,(b)a synthetic retinoid, TAC-101, which is now under phase III clinical trial for the treatment of liver cancer,(c)non-steroidal/non-anilide type structure of androgen antagonists which are active toward so-called anti-androgen-resistant cells (ex.LNCaP cells) bearing point mutated androgen receptor(s),(d)novel vitamin D antagonists (DLAMs) containing a nitrogen atom in their structure,(e)steroid hormone receptor ligands containing a carborane group in their structure.Our studies suggests the wide utility/applicability of the above-mentioned hypothesis for drug design, and the usefulness of thalidomide-related phthalimide/homophtalimide skeleton and diphenylpentane structure as the scaffold of various biologically active compounds and steroid-related active compounds, respectively. Less

设计和制备了各种生物反应调节剂，包括核受体配体（激动剂/拮抗剂）和酶抑制剂，旨在开发治疗慢性疾病（癌症、糖尿病、类风湿病等）的药物。基于其子结构、螺旋12的构象变化的受体以及多模板假说已被提出，(1)配体（激动剂和拮抗剂）。核受体[视黄酸受体 (RAR)、类视黄醇 X 受体 (RXR)、雄激素受体、黄体酮受体、雌激素受体、过氧化物酶体增殖物激活受体 (PPAR)、法尼酯 X 受体 (FXR)、肝 X 受体 (LXR) 和维生素 D 受体，(2) 肿瘤坏死因子 (TNF)-α 产生、微管蛋白聚合的特异性和有效抑制剂，嘌呤霉素敏感氨肽酶 (PSA)、α-葡萄糖苷酶、IV 型二肽基肽酶 (DPP)……更多肿瘤细胞侵袭、组蛋白脱乙酰酶 (HDAC)、乙酰肝素酶、钙调蛋白、环氧合酶 (COX)、氮氧化酶合酶 (NOS)、μ-钙蛋白酶、胸苷磷酸化酶和血管生成已被创建。创建了典型化合物该研究项目包括：(a)一种合成类视黄醇Am80（他米巴罗汀），自2005年起作为治疗急性早幼粒细胞白血病的药物上市，目前正在进行治疗克罗恩病的II期临床试验， (b) 合成类视黄醇 TAC-101，目前正在进行治疗肝癌的 III 期临床试验，(c) 非类固醇/非苯胺类药物雄激素拮抗剂的类型结构，对所谓的抗雄激素抵抗细胞（例如 LNCaP 细胞）具有活性，带有点突变的雄激素受体，（d）结构中含有氮原子的新型维生素 D 拮抗剂（DLAM），(e) 结构中含有碳硼烷基团的类固醇激素受体配体。我们的研究表明上述药物设计假设的广泛实用性/适用性，以及沙利度胺相关的邻苯二甲酰亚胺/高邻苯二甲酰亚胺骨架和二苯基戊烷结构分别作为各种生物活性化合物和类固醇相关活性化合物的支架。