PF-06835919
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MedKoo CAT#: 555163

CAS#: 2102501-84-6

Description: PF-06835919, also known as MDK1846, is a potent ketohexokinase (KHK) inhibitor. PF-06835919 is reported in patent US 20170183328 A1, example 4. Increased fructose consumption and its subsequent metabolism have been implicated in hepatic steatosis, dyslipidemia, obesity, and insulin resistance in humans. Since ketohexokinase (KHK) is the principal enzyme responsible for fructose metabolism, identification of a selective KHK inhibitor may help to further elucidate the effect of KHK inhibition on these metabolic disorders.

Chemical Structure

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PF-06835919
CAS# 2102501-84-6
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 555163
Name: PF-06835919
CAS#: 2102501-84-6
Chemical Formula: C16H19F3N4O2
Exact Mass: 356.15
Molecular Weight: 356.349
Elemental Analysis: C, 53.93; H, 5.37; F, 15.99; N, 15.72; O, 8.98

Price and Availability

Size Price Availability Quantity
1mg USD 150 Ready to ship
5mg USD 450 Ready to ship
10mg USD 750 Ready to ship
25mg USD 1350 Ready to ship
50mg USD 2350 Ready to ship
100mg USD 3850 Ready to ship
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Related CAS #: 2102501-84-6    

Synonym: PF-06835919; PF 06835919; PF06835919; MDK1846; MDK-1846; MDK 1846; ketohexokinase inhibitor; ketohexokinase-In-1

IUPAC/Chemical Name: 2-((1R,5S,6R)-3-(2-((S)-2-methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid

InChi Key: MDUYWDNWFXSMJJ-XWLWVQCSSA-N

InChi Code: InChI=1S/C16H19F3N4O2/c1-8-2-3-23(8)15-20-12(16(17,18)19)5-13(21-15)22-6-10-9(4-14(24)25)11(10)7-22/h5,8-11H,2-4,6-7H2,1H3,(H,24,25)/t8-,9-,10-,11+/m0/s1

SMILES Code: O=C(C[C@@H]1[C@]2(CN(C[C@@]12[H])C3=NC(N4[C@H](CC4)C)=NC(C(F)(F)F)=C3)[H])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

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:

Biological target: Ketohexokinase inhibitor 1 is an inhibitor of ketohexokinase (KHK), with IC50s of 8.4 nM and 66 nM for KHK-C and KHK-A, respectively.
In vitro activity: PF-06835919 showed active uptake in cultured primary human hepatocytes, and substrate activity to organic anion transporter (OAT)2 and organic anion transporting-polypeptide (OATP)1B1 in transfected cells. PF-06835919 showed low intrinsic metabolic clearance in vitro, and was found to be metabolized via both oxidative pathways (58%) and acyl glucuronidation (42%) by CYP3A, CYP2C8, CYP2C9 and UGT2B7. Reference: Drug Metab Dispos. 2022 Jul 2:DMD-AR-2022-000953. https://pubmed.ncbi.nlm.nih.gov/35779864/
In vivo activity: Compared with placebo, significant reductions in WLF were observed in participants receiving PF-06835919 300 mg (difference of -18.73%; p = 0.04), but not with 75 mg. In addition, inhibition of KHK resulted in improvement in inflammatory markers. The incidence of treatment-emergent adverse events (AEs) was low and similar across treatment groups (26.3%, 23.5%, and 29.4% of participants in the placebo and PF-06835919 75 mg and 300 mg groups, respectively). Reference: Med (N Y). 2021 Jul 9;2(7):800-813.e3. https://pubmed.ncbi.nlm.nih.gov/35590219/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 100.0 280.62

Preparing Stock Solutions

The following data is based on the product molecular weight 356.35 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.

Recalculate based on batch purity %
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. Weng Y, Fonseca KR, Bi YA, Mathialagan S, Riccardi K, Tseng E, Bessire AJ, Cerny MA, Tess DA, Rodrigues AD, Kalgutkar AS, Litchfield JE, Di L, Varma MVS. Transporter-Enzyme Interplay in the Pharmacokinetics of PF-06835919, A First-in-class Ketohexokinase Inhibitor for Metabolic Disorders and Non-alcoholic Fatty Liver Disease. Drug Metab Dispos. 2022 Jul 2:DMD-AR-2022-000953. doi: 10.1124/dmd.122.000953. Epub ahead of print. PMID: 35779864. 2. Kazierad DJ, Chidsey K, Somayaji VR, Bergman AJ, Birnbaum MJ, Calle RA. Inhibition of ketohexokinase in adults with NAFLD reduces liver fat and inflammatory markers: A randomized phase 2 trial. Med (N Y). 2021 Jul 9;2(7):800-813.e3. doi: 10.1016/j.medj.2021.04.007. Epub 2021 Apr 27. PMID: 35590219.
In vitro protocol: 1. Weng Y, Fonseca KR, Bi YA, Mathialagan S, Riccardi K, Tseng E, Bessire AJ, Cerny MA, Tess DA, Rodrigues AD, Kalgutkar AS, Litchfield JE, Di L, Varma MVS. Transporter-Enzyme Interplay in the Pharmacokinetics of PF-06835919, A First-in-class Ketohexokinase Inhibitor for Metabolic Disorders and Non-alcoholic Fatty Liver Disease. Drug Metab Dispos. 2022 Jul 2:DMD-AR-2022-000953. doi: 10.1124/dmd.122.000953. Epub ahead of print. PMID: 35779864.
In vivo protocol: 2. Kazierad DJ, Chidsey K, Somayaji VR, Bergman AJ, Birnbaum MJ, Calle RA. Inhibition of ketohexokinase in adults with NAFLD reduces liver fat and inflammatory markers: A randomized phase 2 trial. Med (N Y). 2021 Jul 9;2(7):800-813.e3. doi: 10.1016/j.medj.2021.04.007. Epub 2021 Apr 27. PMID: 35590219.

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1: Saxena AR, Lyle SA, Khavandi K, Qiu R, Whitlock M, Esler WP, Kim AM. A phase 2a, randomized, double-blind, placebo-controlled, 3-arm, parallel-group study to assess the efficacy, safety, tolerability, and pharmacodynamics of PF-06835919 in patients with nonalcoholic fatty liver disease and type 2 diabetes mellitus. Diabetes Obes Metab. 2022 Dec 14. doi: 10.1111/dom.14946. Epub ahead of print. PMID: 36515213.


2: Weng Y, Fonseca KR, Bi YA, Mathialagan S, Riccardi K, Tseng E, Bessire AJ, Cerny MA, Tess DA, Rodrigues AD, Kalgutkar AS, Litchfield JE, Di L, Varma MVS. Transporter-Enzyme Interplay in the Pharmacokinetics of PF-06835919, A First- in-class Ketohexokinase Inhibitor for Metabolic Disorders and Non-alcoholic Fatty Liver Disease. Drug Metab Dispos. 2022 Jul 2:DMD-AR-2022-000953. doi: 10.1124/dmd.122.000953. Epub ahead of print. PMID: 35779864.


3: Kazierad DJ, Chidsey K, Somayaji VR, Bergman AJ, Birnbaum MJ, Calle RA. Inhibition of ketohexokinase in adults with NAFLD reduces liver fat and inflammatory markers: A randomized phase 2 trial. Med (N Y). 2021 Jul 9;2(7):800-813.e3. doi: 10.1016/j.medj.2021.04.007. Epub 2021 Apr 27. PMID: 35590219.


4: Tess DA, Kimoto E, King-Ahmad A, Vourvahis M, Rodrigues AD, Bergman A, Qui R, Somayaji V, Weng Y, Fonseca KR, Litchfield J, Varma MVS. Effect of a Ketohexokinase Inhibitor (PF-06835919) on In Vivo OATP1B Activity: Integrative Risk Assessment Using Endogenous Biomarker and a Probe Drug. Clin Pharmacol Ther. 2022 Sep;112(3):605-614. doi: 10.1002/cpt.2593. Epub 2022 May 9. PMID: 35355249.


5: Gutierrez JA, Liu W, Perez S, Xing G, Sonnenberg G, Kou K, Blatnik M, Allen R, Weng Y, Vera NB, Chidsey K, Bergman A, Somayaji V, Crowley C, Clasquin MF, Nigam A, Fulham MA, Erion DM, Ross TT, Esler WP, Magee TV, Pfefferkorn JA, Bence KK, Birnbaum MJ, Tesz GJ. Pharmacologic inhibition of ketohexokinase prevents fructose-induced metabolic dysfunction. Mol Metab. 2021 Jun;48:101196. doi: 10.1016/j.molmet.2021.101196. Epub 2021 Mar 3. PMID: 33667726; PMCID: PMC8050029.


6: Futatsugi K, Smith AC, Tu M, Raymer B, Ahn K, Coffey SB, Dowling MS, Fernando DP, Gutierrez JA, Huard K, Jasti J, Kalgutkar AS, Knafels JD, Pandit J, Parris KD, Perez S, Pfefferkorn JA, Price DA, Ryder T, Shavnya A, Stock IA, Tsai AS, Tesz GJ, Thuma BA, Weng Y, Wisniewska HM, Xing G, Zhou J, Magee TV. Discovery of PF-06835919: A Potent Inhibitor of Ketohexokinase (KHK) for the Treatment of Metabolic Disorders Driven by the Overconsumption of Fructose. J Med Chem. 2020 Nov 25;63(22):13546-13560. doi: 10.1021/acs.jmedchem.0c00944. Epub 2020 Sep 27. PMID: 32910646.


7: Attia SL, Softic S, Mouzaki M. Evolving Role for Pharmacotherapy in NAFLD/NASH. Clin Transl Sci. 2021 Jan;14(1):11-19. doi: 10.1111/cts.12839. Epub 2020 Aug 25. PMID: 32583961; PMCID: PMC7877845.