21-羟基-17-(1-氧代丙氧基)孕甾-4-烯-3,20-二酮 | 19608-29-8

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 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: 21-羟基-17-(1-氧代丙氧基)孕甾-4-烯-3,20-二酮
• 中文别名: 21-羟基-17-(1-氧代丙氧基)孕甾-4-烯-3,2-二酮
• 英文名称: CB-03-01
• 英文别名: 17α-propionyloxy-21-hydroxy-pregna-4-ene-3,20-dione；21-hydroxy-3,20-dioxopregn-4-en-17-yl propionate；cortexolone 17α-propionate；cortexolone-17α-propionate；Clascoterone；[(8R,9S,10R,13S,14S,17R)-17-(2-hydroxyacetyl)-10,13-dimethyl-3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthren-17-yl] propanoate
• CAS: 19608-29-8
• 化学式: C₂₄H₃₄O₅
• 分子量: 402.531
• InChiKey: GPNHMOZDMYNCPO-PDUMRIMRSA-N

物化性质

• 沸点：
  538.9±50.0 °C(Predicted)
• 密度：
  1.19
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  80.7
• 氢给体数：
  1
• 氢受体数：
  5

ADMET

代谢

根据体外和临床研究，clascoterone的主要可能初级代谢物是cortexolone，这是一种无活性的代谢物。Cortexolone的血浆浓度通常低于或接近定量下限（0.5 ng/mL）。尽管clascoterone能渗透皮肤，但由于皮肤和血浆酯酶（即羧酸酯酶）迅速将clascoterone水解为无活性代谢物，因此该药物的系统性作用是有限的。

According to _in vitro_ and clinical studies, the main possible primary metabolite of clascoterone is cortexolone, which is an inactive metabolite. The plasma concentrations of cortexolone were generally below or near the lower limit of quantitation (0.5 ng/mL). Although clascoterone penetrates the skin, the systemic activity of the drug is limited due to rapid hydrolysis of clascoterone into the inactive metabolite by skin and plasma esterases, namely carboxylesterase.

来源:DrugBank

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：目前没有关于母乳喂养期间使用克林索铜的信息。然而，由于它从皮肤吸收不良并且84%至89%与蛋白结合，母乳中的量可能很低，预计不会对哺乳婴儿造成任何不良影响。避免涂抹在乳头区域，并确保婴儿的皮肤不直接接触已治疗的皮肤区域。 ◉ 对哺乳婴儿的影响：截至修订日期，没有找到相关的已发布信息。 ◉ 对泌乳和母乳的影响：截至修订日期，没有找到相关的已发布信息。

◉ Summary of Use during Lactation:No information is available on the clinical use of clascoterone during breastfeeding. However, because it is poorly absorbed from the skin and 84% to 89% protein bound, amounts in breastmilk are probably low and would not be expected to cause any adverse effects in breastfed infants. Avoid application to the nipple area and ensure that the infant's skin does not come into direct contact with the areas of skin that have been treated. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 蛋白质结合

Clascoterone在体外与血浆蛋白的结合率为84%至89%，且不受药物浓度的影响。

Clascoterone is 84% to 89% bound to plasma proteins _in vitro_, regardless of drug concentrations.

来源:DrugBank

吸收、分配和排泄

• 吸收

经局部应用后，克拉索特龙渗入皮肤到达真皮层，且系统吸收最小。在临床试验中，患有中重度面部寻常痤疮的成年受试者每天两次局部应用六克克拉索特龙。药物达到稳态浓度需五天。两周后，平均±标准差Cmax为4.5 ± 2.9 ng/mL，平均±标准差给药间隔内的血浆浓度-时间曲线下面积（AUCꞇ）为37.1 ± 22.3 h*ng/mL。平均±标准差平均血浆浓度（Cavg）为3.1 ± 1.9 ng/mL。

Upon topical application, clascoteronet permeates the skin to the dermal levels with minimal systemic absorption. In clinical trials, adult subjects with moderate to severe facial acne vulgaris received twice-daily topical application of six grams of clascoterone. The steady-state concentrations of the drug were reached within five days. Following two weeks, the mean ± SD Cmax was 4.5 ± 2.9 ng/mL and the mean ± SD area under the plasma concentration-time over the dosing interval (AUCꞇ) was 37.1 ± 22.3 h*ng/mL. The mean ± SD average plasma concentration (Cavg) was 3.1 ± 1.9 ng/mL.

来源:DrugBank

吸收、分配和排泄

• 消除途径

尚未在人类中完全表征克拉司托龙（clascoterone）的排泄。在局部应用后，克拉司托龙会在表皮层迅速被水解。

Excretion of clascoterone has not been fully characterized in humans. Upon topical application, clascoterone is quickly hydrolyzed in the epidermis.

来源:DrugBank

吸收、分配和排泄

• 分布容积

没有关于分布容积的信息。

There is no information available on the volume of distribution.

来源:DrugBank

吸收、分配和排泄

• 清除

关于克拉司托龙的清除信息有限。

There is limited information on clearance of clascoterone.

来源:DrugBank

安全信息

• 储存条件：
  -20°C，密闭保存，置于干燥处

制备方法与用途

用途

21-羟基-17-(1-氧代丙氧基)孕甾-4-烯-3,20-二酮用于有机合成和医药中间体。

生物活性

Clascoterone (Winlevi、Cortexolone 17α-丙酸酯、Cortexolone 17α-propionate、CB-03-01) 是一种局部和外周选择性的雄激素受体（AR）拮抗剂。

靶点

Target	Value
AR

体内研究

Clascoterone 是一种新的强效外用抗雄激素，可能在治疗寻常性痤疮方面具有潜在价值。1% Clascoterone 软膏表现出很好的耐受性，并且与安慰剂相比，在 TLC（P = 0·0017）、ILC（P = 0·0134）和 ASI（P = 0·0090）方面显著更优，临床效果也优于对照组。此外，该产品还能更快地达到所有上述参数50%的改善。

用途

信号转导通路激酶抑制剂

上下游信息

• 上游原料

  中文名称	英文名称	CAS号	化学式	分子量
  ——	cortexolone 17α,21-dipropionate	19608-30-1	C27H38O6	458.595
  孕甾-4-烯-17Alpha,21-二醇-3,20-二酮-21-醋酸酯	cortexolone 21-acetate	640-87-9	C23H32O5	388.504
  脱氧可的松	Cortexolone	152-58-9	C21H30O4	346.467
  17Alpha-羟基黄体酮	17-hydroxyprogesterone	68-96-2	C21H30O3	330.467

反应信息

• 作为反应物：
  描述：

  21-羟基-17-(1-氧代丙氧基)孕甾-4-烯-3,20-二酮 在 四氯三氧化二磷 作用下， 以 四氢呋喃 为溶剂， 生成
  参考文献：
  名称：

  CN115558013

  摘要：

  公开号：
• 作为产物：
  描述：

  cortexolone 17α,21-dipropionate 以99的产率得到21-羟基-17-(1-氧代丙氧基)孕甾-4-烯-3,20-二酮
  参考文献：
  名称：

  [EN] 17ALFA, 21-DIHYDROXYPREGNENE ESTERS AS ANTIANDROGENIC AGENTS
  [FR] ESTERS DE 17ALFA, 21-DIHYDROXYPREGNENE UTILISES COMME AGENTS ANTIANDROGENES

  摘要：

  17α,21-二羟基孕酮-4,9-二烯-3,20-二酮和17α,21-二羟基孕酮-4-烯-3,20-二酮17和/或21酯具有显著的抗雄激素活性，并且还提供了制备这些化合物的方法。

  公开号：

  WO2003014141A1

文献信息

• [EN] SUBSTITUTED PYRROLOPYRIDINES AS JAK INHIBITORS<br/>[FR] PYRROLOPYRIDINES SUBSTITUÉES EN TANT QU'INHIBITEURS DE JAK
  申请人：ACLARIS THERAPEUTICS INC

  公开号：WO2020223728A1

  公开（公告）日：2020-11-05

  The present invention relates to new pyrrolopyridine compounds having the structures of Formula (I)-(IV), wherein the R groups, A, B, C, D and n are as defined in the detailed description, and compositions and their application as pharmaceuticals for the treatment of disease. Methods of inhibition of JAK kinase activity in a human or animal subject are also provided for the treatment diseases such as pruritus, alopecia, androgenetic alopecia, alopecia areata, vitiligo and psoriasis.

  本发明涉及具有化学式（I）-（IV）结构的新吡咯吡啶化合物，其中R基团，A、B、C、D和n的定义如详细说明中所述，以及这些化合物及其应用作为治疗疾病的药物。还提供了用于治疗疾病如瘙痒症、脱发、雄激素性脱发、斑秃、白癜风和牛皮癣的方法，用于抑制人类或动物主体中JAK激酶活性。
• [EN] POLYMERIC HYPERBRANCHED CARRIER-LINKED PRODRUGS<br/>[FR] PROMÉDICAMENTS LIÉS À DES EXCIPIENTS POLYMÉRIQUES HYPERBRANCHÉS
  申请人：ASCENDIS PHARMA AS

  公开号：WO2013024048A1

  公开（公告）日：2013-02-21

  The present invention relates to water-soluble carrier-linked prodrugs of formula (I),wherein POL is a polymeric moiety,each Hyp is independently a hyperbranched moiety,each moiety SP is independently a spacer moiety, each L is independently a reversible prodrug linker moiety, m is 0 or 1, each n is independently an integer from 2 to 200 and each x is independently 0 or 1. It further relates to pharmaceutical compositions comprising said water- soluble carrier-linked prodrugs and methods of treatment.

  本发明涉及水溶性载体连接的前药，其化学式为（I），其中POL是聚合物基团，每个Hyp是独立的超支化基团，每个基团SP是独立的间隔基团，每个L是独立的可逆前药连接基团，m为0或1，每个n是独立的整数，范围从2到200，每个x是独立的0或1。此外，还涉及包含所述水溶性载体连接的前药的药物组合物和治疗方法。
• [EN] HIGH-LOADING WATER-SOLUBLE CARRIER-LINKED PRODRUGS<br/>[FR] PROMÉDICAMENTS LIÉS À DES EXCIPIENTS HYDROSOLUBLES DE FORTE CHARGE
  申请人：ASCENDIS PHARMA AS

  公开号：WO2013024047A1

  公开（公告）日：2013-02-21

  The present invention relates to water-soluble carrier-linked prodrugs of formula (I), wherein B, A and Hyp form the carrier, B is a branching core, each A is independently a poly(ethylene glycol)-based polymeric chain, each Hyp is independently a branched moiety, each SP is independently a spacer moiety, each L is independently a reversible prodrug linker moiety, each D is independendly a biologically active moiety, each x is independently 0 or 1, each m is independently an integer of from 2 to 64, n is an integer from 3 to 32; or the pharmaceutically acceptable salt thereof. It further relates to pharmaceutical compositions comprising said water-soluble carrier-linked prodrugs, their use asmedicament or diagnostic, and methods of treatment.

  本发明涉及水溶性载体连接的前药，其化学式为(I)，其中B、A和Hyp形成载体，B是一个分支核心，每个A独立地是一条聚乙二醇基聚合链，每个Hyp独立地是一个分支基团，每个SP独立地是一个间隔基团，每个L独立地是一个可逆前药连接基团，每个D独立地是一个生物活性基团，每个x独立地为0或1，每个m独立地是从2到64的整数，n是从3到32的整数；或其药学上可接受的盐。进一步涉及包括所述水溶性载体连接的前药的药物组合物，其用作药物或诊断，以及治疗方法。
• [EN] RELEASABLE CONJUGATES<br/>[FR] CONJUGUÉS LIBÉRABLES
  申请人：QUIAPEG PHARMACEUTICALS AB

  公开号：WO2018163131A1

  公开（公告）日：2018-09-13

  The present application provides compounds of Formula (B), or pharmaceutically acceptable salts thereof, wherein D is a residue of a biologically active drug, which underdo hydrolysis under physiological conditions to release the biologically active drug and which are useful in the treatment of disorders that could be beneficially treated with the drug.

  本申请提供了化合物的公式（B），或其药用盐，其中D是生物活性药物的残留物，在生理条件下经过水解释放出生物活性药物，并且对可能受益于该药物治疗的疾病具有用处。
• [EN] HYDROGEL-LINKED PRODRUGS RELEASING MODIFIED DRUGS<br/>[FR] PROMÉDICAMENTS LIÉS À UN HYDROGEL LIBÉRANT DES MÉDICAMENTS MODIFIÉS
  申请人：ASCENDIS PHARMA AS

  公开号：WO2014173759A1

  公开（公告）日：2014-10-30

  The present invention relates to a process for the preparation of a hydrogel-linked prodrug releasing a tag moiety-bio logically active moiety conjugate, to a hydrogel-linked prodrug releasing a tag moiety-bio logically active moiety conjugate obtainable by such process, to pharmaceutical compositions comprising said prodrug and their use as a medicament.

  本发明涉及一种制备水凝胶连接的前药释放标签基团-生物活性基团结合物的方法，以及通过该方法获得的水凝胶连接的前药释放标签基团-生物活性基团结合物，还涉及包含该前药的药物组合物及其作为药物的用途。