替可的松 | 61951-99-3

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 中文名称: 替可的松
• 中文别名: 硫氢可的松；替可的松-d4
• 英文名称: 11β,17α-dihydroxy-21-mercapto-4-pregnene-3,20-dione
• 英文别名: hydrocortisone；Tixocortol；11β,17-dihydroxy-pregna-4-ene-3,20-dione-21-thiol；(8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-10,13-dimethyl-17-(2-sulfanylacetyl)-2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthren-3-one
• CAS: 61951-99-3
• 化学式: C₂₁H₃₀O₄S
• 分子量: 378.533
• InChiKey: YWDBSCORAARPPF-VWUMJDOOSA-N

物化性质

• 沸点：
  607ºC at 760 mmHg
• 熔点：
  50-55ºC
• 溶解度：
  Insoluble

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  26
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  75.6
• 氢给体数：
  3
• 氢受体数：
  5

ADMET

代谢

Tixocortol在红细胞内迅速被修饰，并且会立即通过首次通过肝脏代谢。Tixocortol的代谢物主要表现为形成磺酸和葡萄糖醛酸共轭物，这些共轭物随后被水解，形成中性类固醇。代谢转化包括3-酮和Δ4系统的还原，C-20羰基团的还原，C-11醇的氧化以及在C-17处侧链的断裂。C-21硫醇酯功能的特定代谢途径是其转化为甲硫基、甲磺酰基和甲磺酰基衍生物，以及C-21-S键的还原断裂，导致21-甲基结构。所有代谢物对糖皮质激素受体没有亲和力。这以及广泛的代谢解释了Tixocortol的独家局部活性。

Tixocortol is rapidly modified within red blood cells and it is immediately metabolized by a first-pass liver metabolism. The metabolites of tixocortol are mainly represented by the formation of sulfo- and glucurono-conjugates which are later hydrolyzed from the conjugate forming neutral steroids. The metabolic transformations are the reduction of the 3-keto and delta 4 system, reduction of the C-20 carbonyl group, oxidation of the C-11 alcohol and cleavage of the side chain at C-17. The specific metabolic pathways of the C-21 thiol ester function were its transformation into methylthio, methylsulfonyl and methylsulfonyl derivatives and reductive cleavage of the C-21-S bond leading to 21-methyl structures. None of the metabolites have affinity for glucocorticoid receptors. This and the extensive metabolism explains the exclusive local activities of tixocortol.

来源:DrugBank

毒理性

• 蛋白质结合

C-17在皮质类固醇中的存在是一个蛋白质结合位点。

The presence of the C-17 in the corticosteroids is a protein binding site.

来源:DrugBank

吸收、分配和排泄

• 吸收

地索考酮的吸收与其他类固醇（包括氢化可的松）相同。口服地索考酮的 生物利用度 为10-20%，血浆Cmax显著低于皮质醇。快速代谢、较大的分布体积和低生物利用度使地索考酮不具有全身活性。

The absorption of tixocortol is the same as in other steroids including hydrocortisone. Oral administration of tixocortol presents a 10-20% bioavailability with a significantly lower plasma Cmax than cortisol. The fast metabolism, larger volume of distribution and low bioavailability donates tixocortol with the absence of systemic activity.

来源:DrugBank

吸收、分配和排泄

• 消除途径

地索科特龙在连续代谢后迅速消除。对地索科特龙的口服给药进行尿液分析显示，未改变药物的完全缺乏。

Tixocortol has a rapid elimination after continuous metabolism. Urine analysis of oral administration of tixocortol demonstrate a complete lack of unchanged drug.

来源:DrugBank

吸收、分配和排泄

• 分布容积

研究表明，与皮质醇相比，口服或静脉注射替索考特尔的分布体积显著较大，为21.7升/千克。

Studies have shown that oral or intravenous administration of tixocortol presents a significantly larger volume of distribution compared to cortisol of 21.7 L/kg.

来源:DrugBank

吸收、分配和排泄

• 清除

研究表明，与皮质醇相比，口服或静脉注射脱氢皮质醇的清除率显著更高，为33.3升/小时/千克。

Studies have shown that oral or intravenous administration of tixocortol presents a significantly larger clearance rate compared to cortisol of 33.3 L h/kg.

来源:DrugBank

反应信息

• 作为反应物：
  描述：

  N-甲酰-L-蛋氨酸 、 替可的松 生成 21-[2-(Formylamino)-4-methylthio-1-oxobutylthio]-11β,17-dihydroxy-pregna-4-ene-3,20-dione
  参考文献：
  名称：

  Steroid compounds

  摘要：

  本发明公开了一种21-取代类固醇化合物。该化合物具有结构式（I），其中R.sup.1是氢原子，较低的烷基，较低的烯基，较低的烷氧基或苯基，R.sup.2是羟基或具有1-6个碳原子的酰氧基，R.sup.3是氢原子或较低的烷基，或R.sup.2和R.sup.3可以共同形成较低的烷基二氧基基团，X.sup.1和X.sup.2可以相同或不同，分别表示氢原子或卤素原子，Y.sup.1和Y.sup.2可以相同或不同，分别表示亚甲基基团或硫原子，Z是硫原子或亚胺基，波浪线表示R.sup.3的构型可以是α或β，1和2位置之间的虚线表示键可能是双键。该化合物具有出色的抗炎，抗过敏和抗哮喘活性，副作用小，可用于预防，治愈和治疗炎症，过敏性疾病，风湿病等。

  公开号：

  US05116829A1
• 作为产物：
  描述：

  S-(2-((8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl) benzothioate 在 sodium hydroxide 作用下， 以 甲醇 为溶剂， 反应 0.5h， 生成 替可的松
  参考文献：
  名称：

  Expeditious synthesis of steroids containing a 2-methylsulfanyl-acetyl side chain as potential glucocorticoid receptor imaging agents

  摘要：

  in our effort to develop imaging agents for brain glucocorticoid receptors, we have prepared several novel glucocorticoids possessing a 2-methylsulfanyl-acetyl side chain. The synthesis was accomplished via a Mitsunobu reaction with thiobenzoic acid starting from cortisol, prednisolone, dexamethasone and triamcinolone acetonide to give the corresponding S-thiobenzoates in 75-82% yield. Subsequent saponification and reaction with methyl iodide afforded C-21 methylthioethers in 68-82% yield. All compounds were tested in an in vitro glucocorticoid receptor-binding assay. Triamcinolone acetonide-based compound 12 showed promising binding affinity of 144% relative to dexamethasone (100%). Compound 12 was selected for radiolabeling with the short-lived positron emitter carbon-11. The radiolabeling was carried out starting from S-thiobenzoate 8 and in situ formation of the corresponding sodium thiolate, which was further reacted with [C-11]methyl iodide. The obtained radiochemical yield was 20-30%. The specific activity was determined to be 20-40 GBq/mu mol at the end-of-synthesis, and the radiochemical purity exceeded 98%. (C) 2007 Elsevier Inc. All rights reserved

  DOI：

  10.1016/j.steroids.2007.08.013

文献信息

• [EN] COMPOUNDS THAT INHIBIT MCL-1 PROTEIN<br/>[FR] COMPOSÉS INHIBANT LA PROTÉINE MCL-1
  申请人：AMGEN INC

  公开号：WO2018183418A1

  公开（公告）日：2018-10-04

  Provided herein are myeloid cell leukemia 1 protein (Mcl-1) inhibitors, methods of their preparation, related pharmaceutical compositions, and methods of using the same. For example, provided herein are compounds of Formula (I), or a stereoisomer thereof; and pharmaceutically acceptable salts thereof and pharmaceutical compositions containing the compounds. The compounds and compositions provided herein may be used, for example, in the treatment of diseases or conditions, such as cancer.

  本文提供了髓样细胞白血病1蛋白（Mcl-1）抑制剂，其制备方法，相关的药物组合物，以及使用这些物质的方法。例如，本文提供了化合物的化学式（I）或其立体异构体；以及这些化合物的药用盐和含有这些化合物的药物组合物。本文提供的化合物和组合物可以用于治疗癌症等疾病或症状。
• [EN] COMPOUNDS USEFUL AS CSF1 MODULATORS<br/>[FR] COMPOSÉS UTILES EN TANT QUE MODULATEURS DU FACTEUR 1 DE STIMULATION DE COLONIES
  申请人：REDX PHARMA PLC

  公开号：WO2016051193A1

  公开（公告）日：2016-04-07

  This invention relates to novel compounds and to pharmaceutical compositions comprising the novel compounds. More specifically, the invention relates to compounds useful as Colony Stimulating Factor 1 Receptor (cFMS) modulators (e.g. cFMS inhibitors). This invention also relates to processes for preparing the compounds, uses of the compounds in treatment and methods of treatment employing the compounds. Specifically, the invention relates to the use of the compounds for the treatment of cancer and autoimmune diseases.

  这项发明涉及新颖化合物以及包含这些新颖化合物的药物组合物。更具体地，该发明涉及用作集落刺激因子1受体（cFMS）调节剂（例如cFMS抑制剂）的化合物。这项发明还涉及制备这些化合物的方法，这些化合物在治疗中的用途以及利用这些化合物进行治疗的方法。具体而言，该发明涉及利用这些化合物治疗癌症和自身免疫性疾病。
• COMPOUNDS THAT MODULATE INTRACELLULAR CALCIUM
  申请人：Whitten Jeffrey P.

  公开号：US20110263612A1

  公开（公告）日：2011-10-27

  Described herein are compounds and pharmaceutical compositions containing such compounds, which modulate the activity of store-operated calcium (SOC) channels. Also described herein are methods of using such SOC channel modulators, alone and in combination with other compounds, for treating diseases or conditions that would benefit from inhibition of SOC channel activity.

  本文描述了含有这些化合物的化合物和药物组合物，这些化合物调节储存操作钙（SOC）通道的活性。本文还描述了使用这种SOC通道调节剂的方法，单独或与其他化合物结合，用于治疗需要抑制SOC通道活性的疾病或症状。
• [EN] DIPEPTIDE AND TRIPEPTIDE EPOXY KETONE PROTEASE INHIBITORS<br/>[FR] INHIBITEURS DE DIPEPTIDE ET DE TRIPEPTIDE ÉPOXY CÉTONE PROTÉASES
  申请人：ONYX THERAPEUTICS INC

  公开号：WO2014152127A1

  公开（公告）日：2014-09-25

  Provided herein are dipeptide and tripeptide epoxy ketone protease inhibitors, methods of their preparation, related pharmaceutical compositions, and methods of using the same. For example, provided herein are compounds of Formula (X): and pharmaceutically acceptable salts and compositions including the same. The compounds and compositions provided herein may be used, for example, in the treatment of proliferative diseases including cancer and autoimmune diseases.

  本文提供了二肽和三肽环氧酮蛋白酶抑制剂，其制备方法，相关的药物组合物，以及使用它们的方法。例如，本文提供了化合物的化学式（X）：及其药用盐和包括这些化合物的组合物。本文提供的化合物和组合物可以用于治疗增生性疾病，包括癌症和自身免疫疾病。
• CYCLODEXTRIN-BASED POLYMERS FOR THERAPEUTIC DELIVERY
  申请人：Cerulean Pharma Inc.

  公开号：US20130196906A1

  公开（公告）日：2013-08-01

  Provided are methods relating to the use of CDP-therapeutic agent conjugates for the treatment of a disease or disorder, e.g., autoimmune disease, inflammatory disease, central nervous system disorder, cardiovascular disease, or metabolic disorder. Also provided are CDP-therapeutic agent conjugates, particles comprising CDP-therapeutic agent conjugates, and compositions comprising CDP-therapeutic agent conjugates.

  提供了关于使用CDP-治疗剂偶联物治疗疾病或紊乱的方法，例如自身免疫疾病、炎症性疾病、中枢神经系统紊乱、心血管疾病或代谢紊乱。还提供了CDP-治疗剂偶联物、包含CDP-治疗剂偶联物的颗粒以及包含CDP-治疗剂偶联物的组合物。