Tazarotenic acid | AGN-190299 | CAS#118292-41-4 | Retinoid Prodrug

MedKoo Cat#: 406552 | Name: Tazarotenic acid

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Description:

WARNING: This product is for research use only, not for human or veterinary use.

Tazarotene is a retinoid prodrug which is converted to its active form, the cognate carboxylic acid of tazarotene (AGN 190299), by rapid deesterification in animals and man. AGN 190299 (“tazarotenic acid”) binds to all three members of the retinoic acid receptor (RAR) family: RARα, RARβ, and RARγ but shows relative selectivity for RARβ, and RARγ and may modify gene expression. The clinical significance of these findings is unknown.

Chemical Structure

Tazarotenic acid

CAS#118292-41-4

Theoretical Analysis

MedKoo Cat#: 406552

Name: Tazarotenic acid

CAS#: 118292-41-4

Chemical Formula: C19H17NO2S

Exact Mass: 323.0980

Molecular Weight: 323.41

Elemental Analysis: C, 70.56; H, 5.30; N, 4.33; O, 9.89; S, 9.91

Price and Availability

Size	Price	Availability
10mg	USD 250.00	2 Weeks
25mg	USD 450.00	2 Weeks
50mg	USD 650.00	2 Weeks
100mg	USD 950.00	2 Weeks

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Related CAS #

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Synonym

AGN 190299; AGN-190299; AGN190299; Tazarotenic acid.

IUPAC/Chemical Name

6-((4,4-dimethylthiochroman-6-yl)ethynyl)nicotinic acid

InChi Key

IQIBKLWBVJPOQO-UHFFFAOYSA-N

InChi Code

InChI=1S/C19H17NO2S/c1-19(2)9-10-23-17-8-4-13(11-16(17)19)3-6-15-7-5-14(12-20-15)18(21)22/h4-5,7-8,11-12H,9-10H2,1-2H3,(H,21,22)

SMILES Code

O=C(O)C1=CN=C(C#CC2=CC(C(C)(C)CCS3)=C3C=C2)C=C1

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO, not in water

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

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Product Data

Product Data

Instruction

View handling instruction

Biological target:

An active metabolite of tazarotene.

In vitro activity:

To determine the effect of tazarotene on cell growth, human BCC cells were treated with various doses of tazarotene for 12, 24, or 48 h, and cell viability was measured using the MTT assay. As shown in Figure 1A, tazarotene significantly reduces BCC cell viability in a dose- and time-dependent manner. To determine whether tazarotene-induced growth inhibition occurs via cell cycle blockade, BCC cells were subjected to flow cytometric analysis. BCC cells were exposed to a series of different tazarotene concentrations for 12, 24, or 48 h. Figure 1B shows that 25 and 50 μM tazarotene treatment for 12 h and 25 μM tazarotene treatment for 24 h caused transient G0/G1 phase cell cycle arrest. In addition, the sub-G1 population, which is typically considered an apoptosis-related hypo-diploid DNA content peak, significantly increased in a dose-dependent manner at 12, 24, and 48 h after tazarotene treatment. To further confirm the observed tazarotene-induced apoptosis, we utilized flow cytometry to analyze TUNEL staining in cells treated with various concentrations of tazarotene for 24 h. As shown in Figure 1C, the percentage of TUNEL-positive BCC cells increased in a concentration-dependent manner. Taken together, these observations suggest that the anti-proliferative effect of tazarotene in BCC cells results, at least in part, from its ability to induce apoptosis. DNA Cell Biol. 2014 Oct;33(10):652-66. https://pubmed.ncbi.nlm.nih.gov/24927175/

In vivo activity:

Therefore, it has been tested whether tazarotene would affect BCCs (basal cell carcinoma) in Ptch1+/− mice in a controlled chemoprevention trial. Consistent with our previous experience (10) , all Ptch1+/− mice treated with vehicle control cream and exposed to UV or IR developed microscopic BCCs (Fig. 1) ⇓ . In the first UV study, Ptch1+/− mice treated topically with 0.1% tazarotene had fewer microscopic BCCs per centimeter of skin surface length than did those in the vehicle control group after 5 months of UV radiation at 7 months of age (1.05 versus 3.9; P < 0.03); after 7 months of UV radiation at 9 months of age (0.46 versus 3.48; P < 0.0001), and after 9 months of UV radiation at 11 months of age (0.51 versus 3.79; P < 0.011; Fig. 1A ⇓ ). The average cross-sectional BCC size in the mice treated with tazarotene was also smaller than that in control animals after 5 months of UV radiation at 7 months of age (2.5 versus 9.1 μm2; P < 0.0001); after 7 months of UV radiation at 9 months of age (2.4 versus 17 μm2; P < 0.0001), and after 9 months of UV radiation at 11 months of age (3.5 versus 54 μm2; P < 0.0023; Fig. 1B ⇓ ). Also, in many skin biopsies, topical tazarotene treatment resulted in a thicker epidermis, as compared with control vehicle-treated mice (Fig. 3) ⇓ . Topical tazarotene treatment did not affect the normal weight gain of the UV- or IR-treated mice (data not shown).Tazarotene is a promising agent for skin cancer prevention in populations at risk for BCCs, such as patients with the basal cell nevus syndrome. Cancer Res. 2004 Jul 1;64(13):4385-9. https://cancerres.aacrjournals.org/content/64/13/4385.long

	Solvent	mg/mL	mM
Solubility
	DMSO	30.0	92.76
	DMF	30.0	92.76
	DMSO:PBS (pH 7.2) (1:4)	0.2	0.62

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 323.41 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Wu CS, Chen GS, Lin PY, Pan IH, Wang ST, Lin SH, Yu HS, Lin CC. Tazarotene induces apoptosis in human basal cell carcinoma via activation of caspase-8/t-Bid and the reactive oxygen species-dependent mitochondrial pathway. DNA Cell Biol. 2014 Oct;33(10):652-66. doi: 10.1089/dna.2014.2366. Epub 2014 Jun 13. PMID: 24927175; PMCID: PMC4179923. 2. Al Haj Zen A, Nawrot DA, Howarth A, Caporali A, Ebner D, Vernet A, Schneider JE, Bhattacharya S. The Retinoid Agonist Tazarotene Promotes Angiogenesis and Wound Healing. Mol Ther. 2016 Oct;24(10):1745-1759. doi: 10.1038/mt.2016.153. Epub 2016 Aug 2. PMID: 27480772; PMCID: PMC5112045. 3. So PL, Lee K, Hebert J, Walker P, Lu Y, Hwang J, Kopelovich L, Athar M, Bickers D, Aszterbaum M, Epstein EH Jr. Topical tazarotene chemoprevention reduces Basal cell carcinoma number and size in Ptch1+/- mice exposed to ultraviolet or ionizing radiation. Cancer Res. 2004 Jul 1;64(13):4385-9. doi: 10.1158/0008-5472.CAN-03-1927. PMID: 15231643. 4. Hsia E, Johnston MJ, Houlden RJ, Chern WH, Hofland HE. Effects of topically applied acitretin in reconstructed human epidermis and the rhino mouse. J Invest Dermatol. 2008 Jan;128(1):125-30. doi: 10.1038/sj.jid.5700968. Epub 2007 Jul 19. PMID: 17637822.

In vitro protocol:

In vivo protocol:

1. So PL, Lee K, Hebert J, Walker P, Lu Y, Hwang J, Kopelovich L, Athar M, Bickers D, Aszterbaum M, Epstein EH Jr. Topical tazarotene chemoprevention reduces Basal cell carcinoma number and size in Ptch1+/- mice exposed to ultraviolet or ionizing radiation. Cancer Res. 2004 Jul 1;64(13):4385-9. doi: 10.1158/0008-5472.CAN-03-1927. PMID: 15231643. 2. Hsia E, Johnston MJ, Houlden RJ, Chern WH, Hofland HE. Effects of topically applied acitretin in reconstructed human epidermis and the rhino mouse. J Invest Dermatol. 2008 Jan;128(1):125-30. doi: 10.1038/sj.jid.5700968. Epub 2007 Jul 19. PMID: 17637822.

1: Foti RS, Isoherranen N, Zelter A, Dickmann LJ, Buttrick BR, Diaz P, Douguet D. Identification of Tazarotenic Acid as the First Xenobiotic Substrate of Human Retinoic Acid Hydroxylase CYP26A1 and CYP26B1. J Pharmacol Exp Ther. 2016 May;357(2):281-92. doi: 10.1124/jpet.116.232637. Epub 2016 Mar 2. PMID: 26937021; PMCID: PMC4851321. 2: Lu YT, Guan R, Zheng JR, Hang TJ, Song M. Determination of clobetasol propionate, tazarotene and tazarotenic acid in Bama mini-pig skin by UPLC-MS/MS: Application to pharmacokinetic and drug-drug interaction studies. J Pharm Biomed Anal. 2020 Jul 15;186:113322. doi: 10.1016/j.jpba.2020.113322. Epub 2020 Apr 23. PMID: 32380355. 3: Attar M, Dong D, Ling KH, Tang-Liu DD. Cytochrome P450 2C8 and flavin- containing monooxygenases are involved in the metabolism of tazarotenic acid in humans. Drug Metab Dispos. 2003 Apr;31(4):476-81. doi: 10.1124/dmd.31.4.476. PMID: 12642475. 4: Sidgiddi S, Allenby K, Okumu F, Gautam A. Bioavailability, Pharmacokinetics, and Transepidermal Water Loss of Short Contact Tazarotene Lotion 0.1% Versus Tazarotene (Tazorac®) Cream 0.1. J Clin Aesthet Dermatol. 2019 Sep;12(9):16-24. Epub 2019 Sep 1. PMID: 31641413; PMCID: PMC6777703. 5: Abramovits W, Abdelmalek N. Treatment of warty dyskeratoma with tazarotenic acid. J Am Acad Dermatol. 2002 Feb;46(2 Suppl Case Reports):S4. doi: 10.1067/mjd.2002.104963. PMID: 11807455. 6: Tong Y, Pan H, Sun C, Xin X, Ding L, Ma P. Simultaneous determination of tazarotene and its active metabolite tazarotenic acid in minipig plasma by LC- MS/MS and its application in pharmacokinetic study after topical administration of tazarotene gel. J Chromatogr B Analyt Technol Biomed Life Sci. 2015 Jan 26;978-979:173-8. doi: 10.1016/j.jchromb.2014.11.030. Epub 2014 Dec 8. PMID: 25550192. 7: Jarratt M, Werner CP, Alió Saenz AB. Tazarotene foam versus tazarotene gel: a randomized relative bioavailability study in acne vulgaris. Clin Drug Investig. 2013 Apr;33(4):283-9. doi: 10.1007/s40261-013-0065-1. PMID: 23456673. 8: Tang-Liu DD, Matsumoto RM, Usansky JI. Clinical pharmacokinetics and drug metabolism of tazarotene: a novel topical treatment for acne and psoriasis. Clin Pharmacokinet. 1999 Oct;37(4):273-87. doi: 10.2165/00003088-199937040-00001. PMID: 10554045. 9: Singh DK, Sahu A, Balhara A, Giri S, Singh S. Insights into the degradation chemistry of tazarotene, a third generation acetylenic retinoid: LC-HRMS (Orbitrap), LC-MSn and NMR characterization of its degradation products, and prediction of their physicochemical and ADMET properties. J Pharm Biomed Anal. 2020 Jul 15;186:113316. doi: 10.1016/j.jpba.2020.113316. Epub 2020 Apr 20. PMID: 32413825. 10: Attar M, Yu D, Ni J, Yu Z, Ling KH, Tang-Liu DD. Disposition and biotransformation of the acetylenic retinoid tazarotene in humans. J Pharm Sci. 2005 Oct;94(10):2246-55. doi: 10.1002/jps.20427. PMID: 16136553. 11: Yu Z, Sefton J, Lew-Kaya D, Walker P, Yu D, Tang-Liu DD. Pharmacokinetics of tazarotene cream 0.1% after a single dose and after repeat topical applications at clinical or exaggerated application rates in patients with acne vulgaris or photodamaged skin. Clin Pharmacokinet. 2003;42(10):921-9. doi: 10.2165/00003088-200342100-00004. PMID: 12885265. 12: Yu Z, Yu D, Walker PS, Tang-Liu DD. Tazarotene does not affect the pharmacokinetics and efficacy of a norethindrone/ethinylestradiol oral contraceptive. Clin Pharmacokinet. 2004;43(10):673-84. doi: 10.2165/00003088-200443100-00003. PMID: 15244497. 13: Duvic M. Pharmacologic profile of tazarotene. Cutis. 1998 Feb;61(2 Suppl):22-6. PMID: 9787988. 14: Li L, Zhang M, Ma P, Qian K. Development of a simple method for simultaneous determination of tazarotene and betamethasone dipropionate and their metabolites using LC-MS method and its application to dermatopharmacokinetic study. Biomed Chromatogr. 2019 Aug;33(8):e4557. doi: 10.1002/bmc.4557. Epub 2019 May 16. PMID: 30990899. 15: Lu YT, Hu ZL, Shao FX, Song M, Hang TJ. Simultaneous determination of tazarotene, clindamycin phosphate and their active metabolites in Bama mini-pig skin by LC-MS/MS: Application to the development of a tazarotene/clindamycin phosphate cream. J Chromatogr B Analyt Technol Biomed Life Sci. 2021 Jan 1;1162:122455. doi: 10.1016/j.jchromb.2020.122455. Epub 2020 Nov 28. PMID: 33360677. 16: Shalita AR, Berson DS, Thiboutot DM, Leyden JJ, Parizadeh D, Sefton J, Walker PS, Gibson JR; Tazarotene Cream in Acne Clinical Study Investigator Group. Effects of tazarotene 0.1 % cream in the treatment of facial acne vulgaris: pooled results from two multicenter, double-blind, randomized, vehicle-controlled, parallel-group trials. Clin Ther. 2004 Nov;26(11):1865-73. doi: 10.1016/j.clinthera.2004.11.012. PMID: 15639698. 17: Menter A. Pharmacokinetics and safety of tazarotene. J Am Acad Dermatol. 2000 Aug;43(2 Pt 3):S31-5. doi: 10.1067/mjd.2000.108321. PMID: 10898827. 18: Madhu C, Duff S, Baumgarten V, Rix P, Small D, Tang-Liu D. Metabolic deesterification of tazarotene in human blood and rat and human liver microsomes. J Pharm Sci. 1997 Aug;86(8):972-4. doi: 10.1021/js9700558. PMID: 9269878. 19: Foti RS, Diaz P, Douguet D. Comparison of the ligand binding site of CYP2C8 with CYP26A1 and CYP26B1: a structural basis for the identification of new inhibitors of the retinoic acid hydroxylases. J Enzyme Inhib Med Chem. 2016;31(sup2):148-161. doi: 10.1080/14756366.2016.1193734. Epub 2016 Jul 17. PMID: 27424662; PMCID: PMC6628712. 20: Marks R. Pharmacokinetics and safety review of tazarotene. J Am Acad Dermatol. 1998 Oct;39(4 Pt 2):S134-8. doi: 10.1016/s0190-9622(98)70310-x. PMID: 9777791.