Indometacin farnesil

Names

[ Name ]:
Indometacin farnesil

[Synonym ]:
(2E,6E)-3,7,11-Trimethyl-2,6,10-dodecatrien-1-yl [1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetate
Infree (TN)
1H-Indole-3-acetic acid, 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-, (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrien-1-yl ester
3,7,11-Trimethyl-2,6,10-dodecatrienyl [1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetate
3,7,11-Trimethyl-2,6,10-dodecatrienyl 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetate
E 0710
1H-Indole-3-acetic acid,1-(4-chlorobenzoyl)-5-methoxy-2-methyl-,3,7,11-trimethyl-2,6,10-dodecatrienyl ester
1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid 3,7,11-trimethyl-2,6,10-dodecatrienyl ester
Indometacin farnesil
Infree
Indomethacin farnesil

Biological Activity

[Description]:

Indomethacin farnesil is an orally active prodrug of Indomethacin. Indomethacin (Indometacin) is a potent, blood-brain permeable and nonselective inhibitor of COX1 and COX2, with IC50s of 18 nM and 26 nM for human COX-1 and COX-2, respectively, in CHO cells. Indomethacin disrupts autophagic flux by disturbing the normal functioning of lysosomes[1][2].

[Related Catalog]:

Signaling Pathways >> Autophagy >> Autophagy

Research Areas >> Inflammation/Immunology

Signaling Pathways >> Immunology/Inflammation >> COX

[In Vitro]

Indometacin farnesil (IMF) is a newly synthesized prodrug of indomethacin designed to reduce the occurrence of side-effects by esterification of the carboxyl group of indomethacin with farnesol. This modification is intended to decrease the extraction and subsequent rapid metabolism of the drug by the liver, so that lymphatic absorption would become a major route, and it was also anticipates that hydrolytic enzymes present in plasma and tissues, including inflamed tissue, would release indomethacin effectively from IMF[2].

[In Vivo]

Indomethacin farnesil (IMF) can effectively release indomethacin when administered locally[1]. Animal Model: Rats[1]. Dosage: 50 nmol a rat paw. Administration: Once. Result: Reduced the level of PGE2 in a dose dependent manner.

[References]

[1]. S Kumakura, et al. Inhibitory effect of indomethacin farnesil, a novel antiinflammatory prodrug, on carrageenin-induced inflammation in rats. Agents Actions. 1990 Mar;29(3-4):286-91.

[2]. M Mishima, et al. Metabolic fate of indometacin farnesil, a prodrug of indomethacin: characteristic biotransformation of indometacin farnesil in rats. Xenobiotica. 1990 Feb;20(2):135-46.

[3]. Riendeau D, et al. Biochemical and pharmacological profile of a tetrasubstituted furanone as a highly selective COX-2 inhibitor. Br J Pharmacol. 1997 May;121(1):105-17.

[4]. Jorge Vallecillo-Hernández, et al. Indomethacin Disrupts Autophagic Flux by Inducing Lysosomal Dysfunction in Gastric Cancer Cells and Increases Their Sensitivity to Cytotoxic Drugs. Sci Rep. 2018 Feb 26;8(1):3593.

Chemical & Physical Properties

[ Density]:
1.1±0.1 g/cm3

[ Boiling Point ]:
626.6±55.0 °C at 760 mmHg

[ Molecular Formula ]:
C₃₄H₄₀ClNO₄

[ Molecular Weight ]:
562.139

[ Flash Point ]:
332.7±31.5 °C

[ Exact Mass ]:
561.264587

[ PSA ]:
57.53000

[ LogP ]:
9.55

[ Vapour Pressure ]:
0.0±1.8 mmHg at 25°C

[ Index of Refraction ]:
1.547

Toxicological Information

CHEMICAL IDENTIFICATION

RTECS NUMBER :: NL3522820

CHEMICAL NAME :: 1H-Indole-3-acetic acid, 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-, 3,7,11-trimethyl-2,6,10- dodecatrienyl ester

CAS REGISTRY NUMBER :: 85801-02-1

LAST UPDATED :: 199506

DATA ITEMS CITED :: 17

MOLECULAR FORMULA :: C34-H40-Cl-N-O4

MOLECULAR WEIGHT :: 562.20

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 1680 mg/kg

TOXIC EFFECTS :: Gastrointestinal - hypermotility, diarrhea

REFERENCE :: YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 17,9,1989

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Intraperitoneal

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 3800 mg/kg

TOXIC EFFECTS :: Gastrointestinal - hypermotility, diarrhea

REFERENCE :: YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 17,9,1989

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Subcutaneous

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 2400 mg/kg

TOXIC EFFECTS :: Gastrointestinal - hypermotility, diarrhea

REFERENCE :: YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 17,9,1989

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Intramuscular

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 2 gm/kg

TOXIC EFFECTS :: Gastrointestinal - hypermotility, diarrhea

REFERENCE :: YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 17,9,1989

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 6800 mg/kg

TOXIC EFFECTS :: Behavioral - somnolence (general depressed activity) Skin and Appendages - hair

REFERENCE :: YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 17,9,1989

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Intraperitoneal

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 1305 mg/kg

TOXIC EFFECTS :: Behavioral - somnolence (general depressed activity) Skin and Appendages - hair

REFERENCE :: YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 17,9,1989

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Subcutaneous

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: >8 gm/kg

TOXIC EFFECTS :: Behavioral - somnolence (general depressed activity) Skin and Appendages - hair

REFERENCE :: YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 17,9,1989

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Intramuscular

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: >4 gm/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

REFERENCE :: YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 17,9,1989

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Mammal - dog

DOSE/DURATION :: >3 gm/kg

TOXIC EFFECTS :: Gastrointestinal - hypermotility, diarrhea Gastrointestinal - nausea or vomiting

REFERENCE :: YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 17,9,1989 ** OTHER MULTIPLE DOSE TOXICITY DATA **

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 9100 mg/kg/13W-I

TOXIC EFFECTS :: Gastrointestinal - ulceration or bleeding from small intestine Blood - normocytic anemia Biochemical - Metabolism (Intermediary) - other proteins

REFERENCE :: YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 17,21,1989

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Mammal - dog

DOSE/DURATION :: 3500 mg/kg/5W-I

TOXIC EFFECTS :: Gastrointestinal - ulceration or bleeding from stomach Gastrointestinal - ulceration or bleeding from small intestine Kidney, Ureter, Bladder - other changes in urine composition

REFERENCE :: YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 17,1481,1989

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Mammal - dog

DOSE/DURATION :: 36500 mg/kg/52-I

TOXIC EFFECTS :: Gastrointestinal - hypermotility, diarrhea Related to Chronic Data - death

REFERENCE :: YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 17,1481,1989 ** REPRODUCTIVE DATA **

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 350 mg/kg

SEX/DURATION :: male 2 week(s) pre-mating female 2 week(s) pre-mating female 1-7 day(s) after conception

TOXIC EFFECTS :: Reproductive - Fertility - pre-implantation mortality (e.g. reduction in number of implants per female; total number of implants per corpora lutea) Reproductive - Effects on Embryo or Fetus - fetal death

REFERENCE :: YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 17,49,1989

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 140 mg/kg

SEX/DURATION :: male 2 week(s) pre-mating

TOXIC EFFECTS :: Reproductive - Fertility - post-implantation mortality (e.g. dead and/or resorbed implants per total number of implants) Reproductive - Effects on Embryo or Fetus - fetal death

REFERENCE :: YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 17,49,1989

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 210 mg/kg

SEX/DURATION :: female 2 week(s) pre-mating female 1-7 day(s) after conception

TOXIC EFFECTS :: Reproductive - Fertility - pre-implantation mortality (e.g. reduction in number of implants per female; total number of implants per corpora lutea)

REFERENCE :: YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 17,49,1989

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 130 mg/kg

SEX/DURATION :: female 17-21 day(s) after conception lactating female 21 day(s) post-birth

TOXIC EFFECTS :: Reproductive - Maternal Effects - parturition Reproductive - Specific Developmental Abnormalities - musculoskeletal system Reproductive - Effects on Newborn - other neonatal measures or effects

REFERENCE :: YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 17,97,1989

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 6500 mg/kg

SEX/DURATION :: female 6-18 day(s) after conception

TOXIC EFFECTS :: Reproductive - Fertility - post-implantation mortality (e.g. dead and/or resorbed implants per total number of implants)

REFERENCE :: YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 17,87,1989

Safety Information

[ Hazard Codes ]:
Xi