PF-04620110 | CAS#1109276-89-2 | DGAT1 inhibitor

MedKoo Cat#: 526744 | Name: PF-04620110

Featured

Description:

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

PF-04620110 is an orally active, selective and potent DGAT1 (Acyl-CoA:diacylglycerol acyltransferase 1) inhibitor that inhibits triacylglycerol synthesis in cells and in rodents. F-04620110 inhibits DGAT-1 with an IC50 of 19 nM and shows high selectivity versus a broad panel of off-target pharmacologic end points. In vivo DGAT-1 inhibition has been demonstrated through reduction of plasma triglyceride levels in rodents at doses of ≥0.1 mg/kg following a lipid challenge. On the basis of this pharmacologic and pharmacokinetic profile, PF-04620110 has been advanced to human clinical studies.

Chemical Structure

PF-04620110

CAS#1109276-89-2

Theoretical Analysis

MedKoo Cat#: 526744

Name: PF-04620110

CAS#: 1109276-89-2

Chemical Formula: C21H24N4O4

Exact Mass: 396.1798

Molecular Weight: 396.45

Elemental Analysis: C, 63.62; H, 6.10; N, 14.13; O, 16.14

Price and Availability

Size	Price	Availability
5mg	USD 250.00
10mg	USD 430.00	2 Weeks
25mg	USD 780.00	2 Weeks

Bulk Inquiry

Buy Now

Add to Cart

Related CAS #

No Data

Synonym

PF-04620110; PF 04620110; PF04620110. PF-4620110; PF 4620110; PF4620110.

IUPAC/Chemical Name

trans-4-[4-(4-Amino-7,8-dihydro-5-oxopyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)phenyl]-cyclohexaneacetic acid

InChi Key

GEVVQZHMFVFGLN-HDJSIYSDSA-N

InChi Code

InChI=1S/C21H24N4O4/c22-19-18-20(24-12-23-19)29-10-9-25(21(18)28)16-7-5-15(6-8-16)14-3-1-13(2-4-14)11-17(26)27/h5-8,12-14H,1-4,9-11H2,(H,26,27)(H2,22,23,24)/t13-,14-

SMILES Code

O=C(O)C[C@H]1CC[C@H](C2=CC=C(N3CCOC4=NC=NC(N)=C4C3=O)C=C2)CC1

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

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-04620110 is a potent, selective and orally bioavailable diglyceride acyltransferase-1 (DGAT-1) inhibitor with an IC50 of 19 nM.

In vitro activity:

PF-04620110 treatment significantly reduced IL-1β and IL-18 secretion in response to PA-BSA compared to vehicle control (Fig. 1A), whereas the secretion of TNF-α, which is an indicator of toll-like receptor 4 (TLR4) signaling [21,22], was unchanged (Fig. 1A). Moreover, PF-04620110 treatment suppressed IL-1β secretion in a dose-dependent manner, in response to PA-BSA relative to vehicle control (Fig. 1B). Similarly, PF-04620110 treatment significantly decreased IL-1β and IL-18 secretion in response to nigericin or ATP, which are other specific activators of NLRP3 inflammasome, compared to vehicle control, whereas the secretion of TNF-α was unchanged (Supplementary Fig. 1). Reference: Diabetes Metab J. 2019 Oct;43(5):683-699. https://pubmed.ncbi.nlm.nih.gov/31694081/

In vivo activity:

To confirm that this pharmacokinetic profile translated into the pharmacodynamic effect via DGAT-1 inhibition in vivo, 3 was evaluated in an acute lipid challenge model measuring plasma triglycerides after a corn oil bolus. Sprague−Dawley rats (n = 7 per dose) were treated with vehicle (5% methyl cellulose), 0.1, 1, or 10 mg/kg of 3 30 min prior to corn oil dosing. Blood samples for triglyceride and pharmacokinetic analyses were taken at 1, 2, and 4 h postlipid challenge. All three doses produced a statistically significant (p < 0.05) reduction in plasma triglyceride excursion at 2 h to near prelipid load levels (Figure (Figure1).1). Reference: ACS Med Chem Lett. 2011 Mar 18;2(5):407-12. https://pubmed.ncbi.nlm.nih.gov/24900321/

	Solvent	mg/mL	mM
Solubility
	DMF	0.2	0.50
	DMSO	7.1	18.02
	DMSO:PBS (pH 7.2) (1:1)	0.5	1.26

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 396.45 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. Jo SI, Bae JH, Kim SJ, Lee JM, Jeong JH, Moon JS. PF-04620110, a Potent Antidiabetic Agent, Suppresses Fatty Acid-Induced NLRP3 Inflammasome Activation in Macrophages. Diabetes Metab J. 2019 Oct;43(5):683-699. doi: 10.4093/dmj.2019.0112. PMID: 31694081; PMCID: PMC6834844. 2. Dow RL, Li JC, Pence MP, Gibbs EM, LaPerle JL, Litchfield J, Piotrowski DW, Munchhof MJ, Manion TB, Zavadoski WJ, Walker GS, McPherson RK, Tapley S, Sugarman E, Guzman-Perez A, DaSilva-Jardine P. Discovery of PF-04620110, a Potent, Selective, and Orally Bioavailable Inhibitor of DGAT-1. ACS Med Chem Lett. 2011 Mar 18;2(5):407-12. doi: 10.1021/ml200051p. PMID: 24900321; PMCID: PMC4018057.

In vitro protocol:

In vivo protocol:

1: Amin NB, Saxena AR, Somayaji V, Dullea R. Inhibition of Diacylglycerol Acyltransferase 2 Versus Diacylglycerol Acyltransferase 1: Potential Therapeutic Implications of Pharmacology. Clin Ther. 2023 Jan;45(1):55-70. doi: 10.1016/j.clinthera.2022.12.008. Epub 2023 Jan 21. PMID: 36690550. 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. 3: Jo SI, Bae JH, Kim SJ, Lee JM, Jeong JH, Moon JS. PF-04620110, a Potent Antidiabetic Agent, Suppresses Fatty Acid-Induced NLRP3 Inflammasome Activation in Macrophages. Diabetes Metab J. 2019 Oct;43(5):683-699. doi: 10.4093/dmj.2019.0112. PMID: 31694081; PMCID: PMC6834844. 4: He F, Zheng W, Chen Y, Mo C, Chen Y. Development and validation of a simple and sensitive high-resolution LC/MS method for determination of PF-04620110 in dog plasma: Application to a pharmacokinetic study. Biomed Chromatogr. 2019 Sep;33(9):e4562. doi: 10.1002/bmc.4562. Epub 2019 Jul 11. PMID: 31017300. 5: Chae YJ, Song JS, Ahn JH, Bae MA, Lee KR. Model-based pharmacokinetic and pharmacodynamic analysis for acute effects of a small molecule inhibitor of diacylglycerol acyltransferase-1 in the TallyHo/JngJ polygenic mouse. Xenobiotica. 2019 Jul;49(7):823-832. doi: 10.1080/00498254.2018.1496303. Epub 2018 Sep 5. PMID: 29972081. 6: Maciejewski BS, Manion TB, Steppan CM. Pharmacological inhibition of diacylglycerol acyltransferase-1 and insights into postprandial gut peptide secretion. World J Gastrointest Pathophysiol. 2017 Nov 15;8(4):161-175. doi: 10.4291/wjgp.v8.i4.161. PMID: 29184702; PMCID: PMC5696614. 7: Dow RL, Andrews MP, Li JC, Michael Gibbs E, Guzman-Perez A, Laperle JL, Li Q, Mather D, Munchhof MJ, Niosi M, Patel L, Perreault C, Tapley S, Zavadoski WJ. Defining the key pharmacophore elements of PF-04620110: discovery of a potent, orally-active, neutral DGAT-1 inhibitor. Bioorg Med Chem. 2013 Sep 1;21(17):5081-97. doi: 10.1016/j.bmc.2013.06.045. Epub 2013 Jul 1. PMID: 23871442. 8: Maciejewski BS, LaPerle JL, Chen D, Ghosh A, Zavadoski WJ, McDonald TS, Manion TB, Mather D, Patterson TA, Hanna M, Watkins S, Gibbs EM, Calle RA, Steppan CM. Pharmacological inhibition to examine the role of DGAT1 in dietary lipid absorption in rodents and humans. Am J Physiol Gastrointest Liver Physiol. 2013 Jun 1;304(11):G958-69. doi: 10.1152/ajpgi.00384.2012. Epub 2013 Apr 4. PMID: 23558010. 9: Lee KR, Choi SH, Song JS, Seo H, Chae YJ, Cho HE, Ahn JH, Ahn SH, Bae MA. Determination of PF-04620110, a novel inhibitor of diacylglycerol acyltransferase-1, in rat plasma using liquid chromatography-tandem mass spectrometry and its application in pharmacokinetic studies. Biomed Chromatogr. 2013 Jul;27(7):846-52. doi: 10.1002/bmc.2869. Epub 2013 Feb 19. PMID: 23420715. 10: Dow RL, Andrews M, Aspnes GE, Balan G, Michael Gibbs E, Guzman-Perez A, Karki K, Laperle JL, Li JC, Litchfield J, Munchhof MJ, Perreault C, Patel L. Design and synthesis of potent, orally-active DGAT-1 inhibitors containing a dioxino[2,3-d]pyrimidine core. Bioorg Med Chem Lett. 2011 Oct 15;21(20):6122-5. doi: 10.1016/j.bmcl.2011.08.028. Epub 2011 Aug 12. PMID: 21908190. 11: Dow RL, Li JC, Pence MP, Gibbs EM, LaPerle JL, Litchfield J, Piotrowski DW, Munchhof MJ, Manion TB, Zavadoski WJ, Walker GS, McPherson RK, Tapley S, Sugarman E, Guzman-Perez A, DaSilva-Jardine P. Discovery of PF-04620110, a Potent, Selective, and Orally Bioavailable Inhibitor of DGAT-1. ACS Med Chem Lett. 2011 Mar 18;2(5):407-12. doi: 10.1021/ml200051p. PMID: 24900321; PMCID: PMC4018057. 12: Macauley D. American Chemical Society-239th national meeting--Investigating new therapeutic candidates: part 1. 21-25 March 2010, San Francisco, CA, USA. IDrugs. 2010 May;13(5):289-91. PMID: 20432180.