PF-06424439 | CAS# 1469284-78-3 | DGAT2 inhibitor

MedKoo Cat#: 522401 | Name: PF-06424439

Description:

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

PF-06424439 is a potent and selective Diacylglycerol Acyltransferase 2 ( DGAT2) inhibitor with DGAT2 IC50 ± SEM (nM) (human/rat/dog) 14 ± 1/38 ± 4/16 ± 1. PF-06424439 demonstrated excellent ADMET properties and decreased circulating and hepatic lipids when orally administered to dyslipidemic rodent models. PF-06424439 inhibited DGAT2 of different species (human, rat, and dog) with similar potency. Among related acyltransferases, no significant inhibition was observed for PF-06424439 (up to 50 μM) against human MGAT2 or MGAT3, DGAT1, or mouse MGAT1, indicating a high selectivity (>2000-fold) against these enzymes.

Chemical Structure

PF-06424439

CAS# 1469284-78-3 (free base)

Theoretical Analysis

MedKoo Cat#: 522401

Name: PF-06424439

CAS#: 1469284-78-3 (free base)

Chemical Formula: C22H26ClN7O

Exact Mass: 439.1887

Molecular Weight: 439.94

Elemental Analysis: C, 60.06; H, 5.96; Cl, 8.06; N, 22.29; O, 3.64

Price and Availability

Size	Price	Availability
50mg	USD 950.00	2 Weeks
100mg	USD 1,650.00	2 Weeks
200mg	USD 2,650.00	2 Weeks
500mg	USD 3,650.00	2 Weeks
1g	USD 4,950.00	2 Weeks
2g	USD 7,950.00	2 Weeks

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Related CAS #

1469284-78-3 (free base) 1469284-80-7 (HCl) 1469284-79-4 (mesylate)

Synonym

PF-06424439; PF06424439; PF 06424439; PF-6424439; PF-6424439; PF 6424439.

IUPAC/Chemical Name

(R)-(1-(2-(1-(4-chloro-1H-pyrazol-1-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone

InChi Key

PZHNKPBYOPQTRG-OAHLLOKOSA-N

InChi Code

InChI=1S/C22H26ClN7O/c23-16-12-24-30(14-16)22(7-8-22)21-25-17-5-6-18(26-19(17)27-21)29-11-3-4-15(13-29)20(31)28-9-1-2-10-28/h5-6,12,14-15H,1-4,7-11,13H2,(H,25,26,27)/t15-/m1/s1

SMILES Code

O=C([C@H]1CN(C2=CC=C3C(NC(C4(N5N=CC(Cl)=C5)CC4)=N3)=N2)CCC1)N6CCCC6

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:

PF-06424439 is a selective imidazopyridine diacylglycerol acyltransferase 2 (DGAT2) inhibitor with an IC50 of 14 nM that is a slowly reversible, time-dependent inhibitor, which inhibits DGAT2 in a noncompetitive mode with respect to the acyl-CoA substrate.

In vitro activity:

The effect of PF-06424439, a selective DGAT2 inhibitor, on MCF7 breast cancer cells exposed to X-rays was evaluated. The results demonstrated that 72 h of PF-06424439 treatment reduced LD (lipid droplets) content and inhibited cell migration, without affecting cell proliferation. Interestingly, PF-06424439 pre-treatment followed by radiation was able to enhance radiosensitivity of MCF7 cells. These findings suggest that PF-06424439 pre-treatment coupled to X-ray exposure might potentiate breast cancer cell radiosensitivity and potentially improve the radiotherapy effectiveness. Reference: Int J Mol Sci. 2021 Sep 18;22(18):10102. https://pubmed.ncbi.nlm.nih.gov/34576263/

In vivo activity:

The effects of DGAT1 and DGAT2 inhibition, alone or in combination, on dietary TAG absorption and diarrhea in mice were investigated by using a selective DGAT1 inhibitor (PF-04620110) and DGAT2 inhibitor (PF-06424439). To further understand relationship between diarrhea and changes in DGAT activity, we examined dose‐dependent effects of DGAT inhibitors in mice. Simultaneous administration of a lower‐dose DGAT1 (0.03 mg/kg) inhibitor, which did not produce maximal effects on intestinal TAG secretion, and the DGAT2 inhibitors significantly decreased plasma radioactivity. These findings suggest that DGAT-mediated intestinal TAG synthesis is a vital step for maintaining intestinal barrier integrity under HFD (high-fat diet) feeding. Reference: Physiol Rep. 2020 Aug;8(15):e14542. https://pubmed.ncbi.nlm.nih.gov/32786057/

	Solvent	mg/mL	mM
Solubility
	DMSO	70.0	159.11
	H2O	70.0	159.11

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 439.94 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. Nisticò C, Pagliari F, Chiarella E, Fernandes Guerreiro J, Marafioti MG, Aversa I, Genard G, Hanley R, Garcia-Calderón D, Bond HM, Mesuraca M, Tirinato L, Spadea MF, Seco JC. Lipid Droplet Biosynthesis Impairment through DGAT2 Inhibition Sensitizes MCF7 Breast Cancer Cells to Radiation. Int J Mol Sci. 2021 Sep 18;22(18):10102. doi: 10.3390/ijms221810102. PMID: 34576263; PMCID: PMC8466244. 2. Takemoto K, Fukasaka Y, Yoshimoto R, Nambu H, Yukioka H. Diacylglycerol acyltransferase 1/2 inhibition induces dysregulation of fatty acid metabolism and leads to intestinal barrier failure and diarrhea in mice. Physiol Rep. 2020 Aug;8(15):e14542. doi: 10.14814/phy2.14542. PMID: 32786057; PMCID: PMC7422801.

In vitro protocol:

In vivo protocol:

1. Takemoto K, Fukasaka Y, Yoshimoto R, Nambu H, Yukioka H. Diacylglycerol acyltransferase 1/2 inhibition induces dysregulation of fatty acid metabolism and leads to intestinal barrier failure and diarrhea in mice. Physiol Rep. 2020 Aug;8(15):e14542. doi: 10.14814/phy2.14542. PMID: 32786057; PMCID: PMC7422801.

1: Almanza A, Mnich K, Blomme A, Robinson CM, Rodriguez-Blanco G, Kierszniowska S, McGrath EP, Le Gallo M, Pilalis E, Swinnen JV, Chatziioannou A, Chevet E, Gorman AM, Samali A. Regulated IRE1α-dependent decay (RIDD)-mediated reprograming of lipid metabolism in cancer. Nat Commun. 2022 May 6;13(1):2493. doi: 10.1038/s41467-022-30159-0. PMID: 35524156; PMCID: PMC9076827. 2: Nisticò C, Pagliari F, Chiarella E, Fernandes Guerreiro J, Marafioti MG, Aversa I, Genard G, Hanley R, Garcia-Calderón D, Bond HM, Mesuraca M, Tirinato L, Spadea MF, Seco JC. Lipid Droplet Biosynthesis Impairment through DGAT2 Inhibition Sensitizes MCF7 Breast Cancer Cells to Radiation. Int J Mol Sci. 2021 Sep 18;22(18):10102. doi: 10.3390/ijms221810102. PMID: 34576263; PMCID: PMC8466244. 3: Takemoto K, Fukasaka Y, Yoshimoto R, Nambu H, Yukioka H. Diacylglycerol acyltransferase 1/2 inhibition induces dysregulation of fatty acid metabolism and leads to intestinal barrier failure and diarrhea in mice. Physiol Rep. 2020 Aug;8(15):e14542. doi: 10.14814/phy2.14542. PMID: 32786057; PMCID: PMC7422801. 4: Mbarik M, Biam RS, Robichaud PP, Surette ME. The impact of PUFA on cell responses: Caution should be exercised when selecting PUFA concentrations in cell culture. Prostaglandins Leukot Essent Fatty Acids. 2020 Apr;155:102083. doi: 10.1016/j.plefa.2020.102083. Epub 2020 Feb 22. PMID: 32126480. 5: Pabst B, Futatsugi K, Li Q, Ahn K. Mechanistic Characterization of Long Residence Time Inhibitors of Diacylglycerol Acyltransferase 2 (DGAT2). Biochemistry. 2018 Dec 26;57(51):6997-7010. doi: 10.1021/acs.biochem.8b01096. Epub 2018 Dec 7. PMID: 30422629. 6: Futatsugi K, Kung DW, Orr ST, Cabral S, Hepworth D, Aspnes G, Bader S, Bian J, Boehm M, Carpino PA, Coffey SB, Dowling MS, Herr M, Jiao W, Lavergne SY, Li Q, Clark RW, Erion DM, Kou K, Lee K, Pabst BA, Perez SM, Purkal J, Jorgensen CC, Goosen TC, Gosset JR, Niosi M, Pettersen JC, Pfefferkorn JA, Ahn K, Goodwin B. Discovery and Optimization of Imidazopyridine-Based Inhibitors of Diacylglycerol Acyltransferase 2 (DGAT2). J Med Chem. 2015 Sep 24;58(18):7173-85. doi: 10.1021/acs.jmedchem.5b01006. PMID: 26349027.

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Description:

Chemical Structure

Theoretical Analysis

Price and Availability

Preparing Stock Solutions

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