化合物信息

ID:742

基本信息

化学结构

分子式

C₄₄H₆₉NO₁₂

分子量

804.01816

精确质量

803.48197665

电荷

InChI

InChI=1S/C44H69NO12/c1-10-13-31-19-25(2)18-26(3)20-37(54-8)40-38(55-9)22-28(5)44(52,57-40)41(49)42(50)45-17-12-11-14-32(45)43(51)56-39(29(6)34(47)24-35(31)48)27(4)21-30-15-16-33(46)36(23-30)53-7/h10,19,21,26,28-34,36-40,46-47,52H,1,11-18,20,22-24H2,2-9H3/b25-19+,27-21+/t26-,28+,29+,30-,31+,32-,33+,34-,36+,37-,38-,39+,40+,44+/m0/s1

InChIKey

QJJXYPPXXYFBGM-LFZNUXCKSA-N

Canonic Smiles

C=CC[C@@H]1/C=C(\C)/C[C@H](C)C[C@H](OC)[C@H]2O[C@](O)([C@@H](C[C@@H]2OC)C)C(=O)C(=O)N2[C@H](C(=O)O[C@@H]([C@@H]([C@H](CC1=O)O)C)/C(=C/[C@@H]1CC[C@H]([C@@H](C1)OC)O)/C)CCCC2

Isomeric Smiles

C(=C\[C@@H]1CC[C@H]([C@@H](C1)OC)O)(/[C@@H]1[C@@H]([C@H](CC(=O)[C@@H](/C=C(\C)/C[C@H](C)C[C@@H]([C@@H]2[C@H](C[C@H]([C@](O2)(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1)C)OC)OC)CC=C)O)C)\C

计算属性

JChem

Acid pKa

9.955601

质子受体

质子供体

LogD (pH = 5.5)

5.594105

LogD (pH = 7.4)

5.5929146

Log P

5.59412

摩尔折射率

215.6203

极化性

84.94902

极化表面积

178.36

可自由旋转的化学键

里宾斯基五规则

false

ALOGPS 2.1

Log P

3.19

LOG S

-5.3

溶解度

4.02e-03 g/l

数据来源

学术数据

产品目录

数据来源

名称和标识

商标名

LCP-TacroProtopicFujimycinPrograf

别名

FK5tacrolimus hydrateTacrolimusFK-506TacarolimusK506tacrolimusPrografFK-506Fujimycin

IUPAC标准名

(1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-1,14-dihydroxy-12-[(1E)-1-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]prop-1-en-2-yl]-23,25-dimethoxy-13,19,21,27-tetramethyl-17-(prop-2-en-1-yl)-11,28-dioxa-4-azatricyclo[22.3.1.0^{4,9}]octacos-18-ene-2,3,10,16-tetrone

IUPAC传统名

tsukubaenolide

名称和标识

数据登录号

CAS号

104987-11-3

PubChem SID

46506004160964205

PubChem CID

445647445643

数据登录号

化合物性质

理化性质

疏水性(logP)

3.3

溶解度

Insoluble

DMSO

产品相关信息

成盐信息

Free Base

安全信息

保存条件

-20°C

化合物性质

分子相关蛋白质

暂无数据

点击上传数据

分子图谱

暂无数据

点击上传数据

描述信息

DrugBank

DB00864

Drug Groups

approved; investigational

Description

Tacrolimus (also FK-506 or Fujimycin) is an immunosuppressive drug whose main use is after organ transplant to reduce the activity of the patient's immune system and so the risk of organ rejection. It is also used in a topical preparation in the treatment of severe atopic dermatitis, severe refractory uveitis after bone marrow transplants, and the skin condition vitiligo. It was discovered in 1984 from the fermentation broth of a Japanese soil sample that contained the bacteria Streptomyces tsukubaensis. Tacrolimus is chemically known as a macrolide. It reduces peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP-12 (FK506 binding protein) creating a new complex. This FKBP12-FK506 complex interacts with and inhibits calcineurin thus inhibiting both T-lymphocyte signal transduction and IL-2 transcription.

Indication

For use after allogenic organ transplant to reduce the activity of the patient's immune system and so the risk of organ rejection. It was first approved by the FDA in 1994 for use in liver transplantation, this has been extended to include kidney, heart, small bowel, pancreas, lung, trachea, skin, cornea, and limb transplants. It has also been used in a topical preparation in the treatment of severe atopic dermatitis.

Pharmacology

Tacrolimus is a macrolide antibiotic. It acts by reducing peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP-12 (FK506 binding protein) creating a new complex. This inhibits both T-lymphocyte signal transduction and IL-2 transcription. Although this activity is similar to cyclosporine studies have shown that the incidence of acute rejection is reduced by tacrolimus use over cyclosporine. Tacrolimus has also been shown to be effective in the topical treatment of eczema, particularly atopic eczema. It suppresses inflammation in a similar way to steroids, but is not as powerful. An important dermatological advantage of tacrolimus is that it can be used directly on the face; topical steroids cannot be used on the face, as they thin the skin dramatically there. On other parts of the body, topical steroid are generally a better treatment.

Toxicity

Side effects can be severe and include blurred vision, liver and kidney problems (it is nephrotoxic), seizures, tremors, hypertension, hypomagnesemia, diabetes mellitus, hyperkalemia, itching, insomnia, confusion. LD₅₀=134-194 mg/kg (rat).

Affected Organisms

Humans and other mammals

Biotransformation

Hepatic, extensive, primarily by CYP3A4. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus.

Absorption

20% bioavailability; less after eating food rich in fat

Half Life

11.3 hours (range from 3.5 to 40.6 hours)

Protein Binding

75-99%

Elimination

In man, less than 1% of the dose administered is excreted unchanged in urine. Fecal elimination accounted for 92.6±30.7%, urinary elimination accounted for 2.3±1.1%.

Distribution

* 2.6±2.1 L/kg [pediatric patients]

Clearance

* 0.029 +/- 0.009 L/hr/kg [healthy subjects IV administered]
* 0.172 +/- 0.088 L/hr/kg [Healthy subjects administered PO]
* 0.138 +/- 0.071 L/hr/kg [liver transplantation pediatric patients]
* 0.038 +/-0.014 L/hr/kg [patients with renal impairment 0.02 mg/kg/4 hr, IV]
* 0.042 +/- 0.02 L/hr/kg [Mild Hepatic Impairment 0.02 mg/kg/4 hr, IV]
* 0.034 +/- 0.019 L/hr/kg [Mild Hepatic Impairment 7.7 mg PO]
* 0.017 +/- 0.013 L/hr/kg [Severe hepatic impairement 0.02 mg/kg/4 hr, IV]

References

• Kino T, Hatanaka H, Hashimoto M, Nishiyama M, Goto T, Okuhara M, Kohsaka M, Aoki H, Imanaka H: FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot (Tokyo). 1987 Sep;40(9):1249-55. [Pubmed]

• Pritchard DI: Sourcing a chemical succession for cyclosporin from parasites and human pathogens. Drug Discov Today. 2005 May 15;10(10):688-91. [Pubmed]

• Liu J, Farmer JD Jr, Lane WS, Friedman J, Weissman I, Schreiber SL: Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991 Aug 23;66(4):807-15. [Pubmed]

• Fukatsu S, Fukudo M, Masuda S, Yano I, Katsura T, Ogura Y, Oike F, Takada Y, Inui K: Delayed effect of grapefruit juice on pharmacokinetics and pharmacodynamics of tacrolimus in a living-donor liver transplant recipient. Drug Metab Pharmacokinet. 2006 Apr;21(2):122-5. [Pubmed]

• Hanifin JM, Paller AS, Eichenfield L, Clark RA, Korman N, Weinstein G, Caro I, Jaracz E, Rico MJ: Efficacy and safety of tacrolimus ointment treatment for up to 4 years in patients with atopic dermatitis. J Am Acad Dermatol. 2005 Aug;53(2 Suppl 2):S186-94. [Pubmed]

External Links

• [Wikipedia]

• [RxList]

• [Drugs.com]

Selleck Chemicals

S5003

Research Area: Immunology
Biological Activity:
FK-506 inhibits Ca2+-dependent transcription of lymphokine genes in T cells.FK-506 (0.1 to 300 nM) concentration dependently inhibited histamine release from lung parenchymal mast cells activated by anti-IgE. FK-506 was more potent in lung mast cells than in basophils (IC50 = 1.13 +/- 0.46 nM vs 5.28 +/- 0.88 nM; p less than 0.001), whereas the maximal inhibitory effect was higher in basophils than in lung mast cells (88.4 +/- 2.5% vs 76.4 +/- 3.8%; p less than 0.01). [2]FK-506 (1 to 300 nM) concentration dependently inhibited histamine release from basophils activated by Der p I Ag, anti-IgE, or compound A23187. FK-506 was more potent than CsA when basophils were challenged with Ag (IC50 = 25.5 +/- 9.5 vs 834.3 +/- 79.8 nM; p less than 0.001), anti-IgE (IC50 = 9.4 +/- 1.7 vs 441.3 +/- 106.7 nM; p less than 0.001), and A23187 (IC50 = 4.1 +/- 0.9 vs 36.7 +/- 3.8 nM; p less than 0.001). The maximal inhibitory effect of FK-506 was higher than that caused by CsA when basophils were activated by Der p I (80.0 +/- 3.6 vs 49.5 +/- 4.7%; p less than 0.001) and anti-IgE (90.4 +/- 1.8 vs 62.3 +/- 2.9%; p less than 0.001). [3]

描述信息

参考文献

PubChem文献

数据源提供

• Liu J, Farmer JD Jr, Lane WS, Friedman J, Weissman I, Schreiber SL: Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991 Aug 23;66(4):807-15. Pubmed

• Pritchard DI: Sourcing a chemical succession for cyclosporin from parasites and human pathogens. Drug Discov Today. 2005 May 15;10(10):688-91. Pubmed

• A de Paulis et al.J Immunol.1991; 146: 2374-2381

参考文献

生物活性

PubChem BioAssay

生物活性

导航

基本信息

计算属性

• RDKit

• JChem

• ALOGPS 2.1

数据来源

• 学术数据

• 产品目录

名称和标识

• 商标名

• 别名

• IUPAC标准名

• IUPAC传统名

数据登录号

• CAS号

• PubChem SID

• PubChem CID

化合物性质

• 理化性质

• 产品相关信息

• 安全信息

分子相关蛋白质

分子图谱

描述信息

• DrugBank

• Selleck Chemicals

参考文献

• PubChem文献

• 数据源提供

生物活性

• PubChem BioAssay

商标名

LCP-TacroProtopicFujimycinPrograf

别名

FK5tacrolimus hydrateTacrolimusFK-506TacarolimusK506tacrolimusPrografFK-506Fujimycin

IUPAC标准名

IUPAC传统名

tsukubaenolide

PubChem SID

46506004160964205

PubChem CID

445647445643

理化性质

疏水性(logP)

3.3

溶解度

Insoluble

DMSO

产品相关信息

成盐信息

Free Base

安全信息

保存条件

-20°C

DrugBank

DB00864

Drug Groups

approved; investigational

Description

Indication

Pharmacology

Toxicity

Affected Organisms

Humans and other mammals

Biotransformation

Absorption

20% bioavailability; less after eating food rich in fat

Half Life

11.3 hours (range from 3.5 to 40.6 hours)

Protein Binding

75-99%

Elimination

In man, less than 1% of the dose administered is excreted unchanged in urine. Fecal elimination accounted for 92.6±30.7%, urinary elimination accounted for 2.3±1.1%.

Distribution

* 2.6±2.1 L/kg [pediatric patients]

Clearance

References

• Pritchard DI: Sourcing a chemical succession for cyclosporin from parasites and human pathogens. Drug Discov Today. 2005 May 15;10(10):688-91. [Pubmed]

• Liu J, Farmer JD Jr, Lane WS, Friedman J, Weissman I, Schreiber SL: Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991 Aug 23;66(4):807-15. [Pubmed]

External Links

• [Wikipedia]

• [RxList]

• [Drugs.com]

Selleck Chemicals

S5003

数据源提供

• Liu J, Farmer JD Jr, Lane WS, Friedman J, Weissman I, Schreiber SL: Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991 Aug 23;66(4):807-15. Pubmed

• Pritchard DI: Sourcing a chemical succession for cyclosporin from parasites and human pathogens. Drug Discov Today. 2005 May 15;10(10):688-91. Pubmed

• A de Paulis et al.J Immunol.1991; 146: 2374-2381