Ponalrestat | ICI-128436 | MK-538 | CAS#72702-95-5 | Aldose reductase inhibitor

MedKoo Cat#: 319607 | Name: Ponalrestat

Description:

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

Ponalrestat, also known as MK-538, is an aldose reductase inhibitor. Ponalrestat inhibits cachexia syndrome induced by colon26 adenocarcinoma in mice. Ponalrestat activates lipoprotein lipase (LPL) activity in the adipose tissue and alleviates the cachectic symptoms induced by B16 melanoma in mice. Ponalrestat is effective in the attenuation of the cachectic symptoms induced by human melanomas G361 and SEKI in nude mice, suggesting that ponalrestat has a potential usefulness for the treatment of cancer cachexia.

Chemical Structure

Ponalrestat

CAS#72702-95-5

Theoretical Analysis

MedKoo Cat#: 319607

Name: Ponalrestat

CAS#: 72702-95-5

Chemical Formula: C17H12BrFN2O3

Exact Mass: 390.0015

Molecular Weight: 391.20

Elemental Analysis: C, 52.20; H, 3.09; Br, 20.43; F, 4.86; N, 7.16; O, 12.27

Price and Availability

Size	Price	Availability
100mg	USD 950.00	2 Weeks
200mg	USD 1,650.00	2 Weeks
500mg	USD 2,150.00	2 Weeks
1g	USD 3,450.00	2 Weeks
2g	USD 4,650.00	2 Weeks
5g	USD 7,650.00	2 Weeks

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Synonym

Ponalrestat, ICI-128436; ICI 128436; ICI128436; MK-538; MK 538; MK538. Brand name: Statil; Statyl.

IUPAC/Chemical Name

2-(3-(4-bromo-2-fluorobenzyl)-4-oxo-3,4-dihydrophthalazin-1-yl)acetic acid

InChi Key

LKBFFDOJUKLQNY-UHFFFAOYSA-N

InChi Code

InChI=1S/C17H12BrFN2O3/c18-11-6-5-10(14(19)7-11)9-21-17(24)13-4-2-1-3-12(13)15(20-21)8-16(22)23/h1-7H,8-9H2,(H,22,23)

SMILES Code

O=C(O)CC1=NN(CC2=CC=C(Br)C=C2F)C(C3=C1C=CC=C3)=O

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

More Info

Product Data

Product Data

Instruction

View handling instruction

Biological target:

Ponalrestat (ICI 128436) is an orally active, selective and noncompetitive aldose reductase (AKR1B1; ALR) inhibitor.

In vitro activity:

This study found that ponalrestat exposure recovers root elongation in these mutants in an ethylene signal-independent manner. Genetic and pharmacological investigations revealed that ponalrestat inhibits the enzymatic activity of the flavin-containing monooxygenase YUCCA, which catalyzes the rate-limiting step of the indole-3-pyruvic acid branch of the auxin biosynthesis pathway. Reference: J Biol Chem. 2019 Dec 27;294(52):19923-19933. https://pubmed.ncbi.nlm.nih.gov/31732559/

In vivo activity:

In this study, the effect of ponalrestat on murine adenocarcinoma colon26-induced cachexia was investigated in mice. Mice bearing colon26 subcutaneously lost weight and became cachectic, associated with the tumor growth. Although tumor growth was slightly stimulated when tumor bearing mice were treated with ponalrestat: nevertheless, the drug attenuated the reduction in the weight of body mass, epididymal fat, gastrocnemius muscle and carcass induced by colon26, as well as significantly prolonged the survival of the colon26 bearing mice. Reference: Anticancer Res. 1999 Sep-Oct;19(5B):4105-11. https://pubmed.ncbi.nlm.nih.gov/10628361/

	Solvent	mg/mL	mM
Solubility
	DMF	2.0	5.11
	DMSO	32.3	82.44
	Ethanol	2.0	5.11
	PBS (pH 7.2)	0.2	0.51

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 391.20 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. Zhu Y, Li HJ, Su Q, Wen J, Wang Y, Song W, Xie Y, He W, Yang Z, Jiang K, Guo H. A phenotype-directed chemical screen identifies ponalrestat as an inhibitor of the plant flavin monooxygenase YUCCA in auxin biosynthesis. J Biol Chem. 2019 Dec 27;294(52):19923-19933. doi: 10.1074/jbc.RA119.010480. Epub 2019 Nov 15. PMID: 31732559; PMCID: PMC6937590. 2. Michaud A, Lacroix-Pépin N, Pelletier M, Veilleux A, Noël S, Bouchard C, Marceau P, Fortier MA, Tchernof A. Prostaglandin (PG) F2 alpha synthesis in human subcutaneous and omental adipose tissue: modulation by inflammatory cytokines and role of the human aldose reductase AKR1B1. PLoS One. 2014 Mar 24;9(3):e90861. doi: 10.1371/journal.pone.0090861. PMID: 24663124; PMCID: PMC3963845. 3. Kawamura I, Lacey E, Yamamoto N, Sakai F, Takeshita S, Inami M, Nishigaki F, Naoe Y, Tsujimoto S, Manda T, Shimomura K, Goto T. Ponalrestat, an aldose reductase inhibitor, inhibits cachexia syndrome induced by colon26 adenocarcinoma in mice. Anticancer Res. 1999 Sep-Oct;19(5B):4105-11. PMID: 10628361. 4. Kawamura I, Lacey E, Inami M, Nishigaki F, Naoe Y, Tsujimoto S, Manda T, Goto T. Ponalrestat, an aldose reductase inhibitor, inhibits cachexia syndrome in nude mice bearing human melanomas G361 and SEKI. Anticancer Res. 1999 Sep-Oct;19(5B):4091-7. PMID: 10628359.

In vitro protocol:

In vivo protocol:

1. Kawamura I, Lacey E, Yamamoto N, Sakai F, Takeshita S, Inami M, Nishigaki F, Naoe Y, Tsujimoto S, Manda T, Shimomura K, Goto T. Ponalrestat, an aldose reductase inhibitor, inhibits cachexia syndrome induced by colon26 adenocarcinoma in mice. Anticancer Res. 1999 Sep-Oct;19(5B):4105-11. PMID: 10628361. 2. Kawamura I, Lacey E, Inami M, Nishigaki F, Naoe Y, Tsujimoto S, Manda T, Goto T. Ponalrestat, an aldose reductase inhibitor, inhibits cachexia syndrome in nude mice bearing human melanomas G361 and SEKI. Anticancer Res. 1999 Sep-Oct;19(5B):4091-7. PMID: 10628359.

1: Kawamura I, Lacey E, Yamamoto N, Sakai F, Takeshita S, Inami M, Nishigaki F, Naoe Y, Tsujimoto S, Manda T, Shimomura K, Goto T. Ponalrestat, an aldose reductase inhibitor, inhibits cachexia syndrome induced by colon26 adenocarcinoma in mice. Anticancer Res. 1999 Sep-Oct;19(5B):4105-11. PubMed PMID: 10628361. 2: Kawamura I, Lacey E, Inami M, Nishigaki F, Naoe Y, Tsujimoto S, Manda T, Goto T. Ponalrestat, an aldose reductase inhibitor, inhibits cachexia syndrome in nude mice bearing human melanomas G361 and SEKI. Anticancer Res. 1999 Sep-Oct;19(5B):4091-7. PubMed PMID: 10628359. 3: Kawamura I, Yamamoto N, Sakai F, Yamazaki H, Naoe Y, Inami M, Manda T, Shimomura K. Activation of lipoprotein lipase and inhibition of B16 melanoma-induced cachexia in mice by ponalrestat, an aldose reductase inhibitor. Anticancer Res. 1999 Jan-Feb;19(1A):341-8. PubMed PMID: 10226565. 4: Laudadio C, Sima AA. Progression rates of diabetic neuropathy in placebo patients in an 18-month clinical trial. Ponalrestat Study Group. J Diabetes Complications. 1998 May-Jun;12(3):121-7. PubMed PMID: 9618066. 5: Otter DJ, Chess-Williams R. The effects of aldose reductase inhibition with ponalrestat on changes in vascular function in streptozotocin diabetic rats. Br J Pharmacol. 1994 Oct;113(2):576-80. PubMed PMID: 7834210; PubMed Central PMCID: PMC1510137. 6: Taylor PD, Wickenden AD, Mirrlees DJ, Poston L. Endothelial function in the isolated perfused mesentery and aortae of rats with streptozotocin-induced diabetes: effect of treatment with the aldose reductase inhibitor, ponalrestat. Br J Pharmacol. 1994 Jan;111(1):42-8. PubMed PMID: 8012723; PubMed Central PMCID: PMC1910054. 7: Reddi AS, Jyothirmayi GN. Aldose reductase inhibition by ponalrestat (statil) does not prevent proteinuria in long-term diabetic rats. J Diabetes Complications. 1993 Oct-Dec;7(4):233-40. PubMed PMID: 8219366. 8: Boland OM, Blackwell CC, Clarke BF, Ewing DJ. Effects of ponalrestat, an aldose reductase inhibitor, on neutrophil killing of Escherichia coli and autonomic function in patients with diabetes mellitus. Diabetes. 1993 Feb;42(2):336-40. PubMed PMID: 8425670. 9: Cameron NE, Cotter MA. Dissociation between biochemical and functional effects of the aldose reductase inhibitor, ponalrestat, on peripheral nerve in diabetic rats. Br J Pharmacol. 1992 Dec;107(4):939-44. PubMed PMID: 1467842; PubMed Central PMCID: PMC1907934. 10: Krentz AJ, Honigsberger L, Ellis SH, Hardman M, Nattrass M. A 12-month randomized controlled study of the aldose reductase inhibitor ponalrestat in patients with chronic symptomatic diabetic neuropathy. Diabet Med. 1992 Jun;9(5):463-8. PubMed PMID: 1611835. 11: Arauz-Pacheco C, Ramirez LC, Pruneda L, Sanborn GE, Rosenstock J, Raskin P. The effect of the aldose reductase inhibitor, ponalrestat, on the progression of diabetic retinopathy. J Diabetes Complications. 1992 Apr-Jun;6(2):131-7. PubMed PMID: 1611137. 12: Sundkvist G, Armstrong FM, Bradbury JE, Chaplin C, Ellis SH, Owens DR, Rosén I, Sönksen P. Peripheral and autonomic nerve function in 259 diabetic patients with peripheral neuropathy treated with ponalrestat (an aldose reductase inhibitor) or placebo for 18 months. United Kingdom/Scandinavian Ponalrestat Trial. J Diabetes Complications. 1992 Apr-Jun;6(2):123-30. PubMed PMID: 1611136. 13: Beyer-Mears A, Murray FT, Cruz E, Rountree J, Sciadini M. Comparison of sorbinil and ponalrestat (Statil) diminution of proteinuria in the BB rat. Pharmacology. 1992;45(5):285-91. PubMed PMID: 1465475. 14: Williams M, Mayhew TM. Responses of enterocyte microvilli in experimental diabetes to insulin and an aldose reductase inhibitor (ponalrestat). Virchows Arch B Cell Pathol Incl Mol Pathol. 1992;62(6):385-9. PubMed PMID: 1360726. 15: Ziegler D, Mayer P, Rathmann W, Gries FA. One-year treatment with the aldose reductase inhibitor, ponalrestat, in diabetic neuropathy. Diabetes Res Clin Pract. 1991 Oct;14(1):63-73. PubMed PMID: 1748064. 16: Moulds RF, Fullinfaw RO, Bury RW, Plehwe WE, Jacka N, McGrath KM, Martin FI. Ponalrestat does not cause a protein binding interaction with warfarin in diabetic patients. Br J Clin Pharmacol. 1991 Jun;31(6):715-8. PubMed PMID: 1907841; PubMed Central PMCID: PMC1368588. 17: Ramirez LC, Arauz C, Pruneda L, Hammon K, Rosenstock J, Raskin P. The effect of aldose reductase inhibition with ponalrestat on the width of the capillary basement membrane in diabetes mellitus. Diabetes Res Clin Pract. 1991 Feb;11(2):73-80. PubMed PMID: 1902410. 18: Austin CE, Chess-Williams R. Diabetes-induced changes in cardiac beta-adrenoceptor responsiveness: effects of aldose reductase inhibition with ponalrestat. Br J Pharmacol. 1991 Feb;102(2):478-82. PubMed PMID: 1849772; PubMed Central PMCID: PMC1918039. 19: Florkowski CM, Rowe BR, Nightingale S, Harvey TC, Barnett AH. Clinical and neurophysiological studies of aldose reductase inhibitor ponalrestat in chronic symptomatic diabetic peripheral neuropathy. Diabetes. 1991 Jan;40(1):129-33. PubMed PMID: 1901808. 20: Pekiner C, McLean WG. Impaired induction of nerve ornithine decarboxylase activity in the streptozotocin-diabetic rat is prevented by the aldose reductase inhibitor ponalrestat. Br J Pharmacol. 1990 Dec;101(4):978-80. PubMed PMID: 2128196; PubMed Central PMCID: PMC1917828.

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