In vitro: PF-05175157 is not metabolized in rat, dog, or human microsomes. PF-05175157 is also stable in human hepatocyte incubations, but is minimally metabolized by recombinant human CYP3A4 and CYP3A5. PF-05175157 inhibits formation of malonyl-CoA in a concentration-dependent manner with a potency (EC50=30 nM) in rat hepatocytes consistent with its potency against rat ACC1 (24 nM).
In vivo: Oral administration (3 mg/kg) to rats and dogs show bioavailability of 40% and 54%, respectively, consistent with the low microsomal clearance and good solubility at low pH. Formation of the direct product of ACC, malonyl-CoA, in the skeletal muscle and liver of lean rats is assessed 1 h following an acute oral dose of PF-05175157, showing concentration-dependent reductions in both skeletal muscle and liver malonyl-CoA. At the nadir, quadriceps and liver malonyl-CoA levels are reduced by 76% and 89%, respectively. The EC50s for inhibition of quadriceps and liver malonyl-CoA are 870 and 540 nM, respectively, determined from unbind plasma concentrations of PF-05175157. Acute oral administration of PF-05175157 inhibits hepatic DNL in rats in an unbind plasma drug concentration-dependent manner. PF-05175157 inhibits up to 82% of the incorporation of [14C]acetate into [14C]lipids with an EC50 of 326 nM.
Drug Dev Res. 2023 Aug 11.
FAM64A aggravates proliferation, invasion, lipid droplet formation, and chemoresistance in gastric cancer: A biomarker for aggressiveness and a gene therapy target
PF-05175157 purchased from AbMole
World J Gastroenterol. 2023 Sep 21;29(35): 5104-5124.
Regenerating gene 4 promotes chemoresistance of colorectal cancer by affecting lipid droplet synthesis and assembly
PF-05175157 purchased from AbMole
| Cell Experiment | |
|---|---|
| Cell lines | |
| Preparation method | |
| Concentrations | |
| Incubation time | |
| Animal Experiment | |
|---|---|
| Animal models | Male SD rats |
| Formulation | 0.5% methyl cellulose: 0.1% polysorbate 80 |
| Dosages | 0.25, 0.5, 1, 2, 4, 8, 15, 25, 50, and 100 mg/kg |
| Administration | oral |
| Molecular Weight | 405.49 |
| Formula | C23H27N5O2 |
| CAS Number | 1301214-47-0 |
| Solubility (25°C) | 30 mg/mL in DMSO |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
| Related Acetyl-CoA Carboxylase Products |
|---|
| Sethoxydim
Sethoxydim is a postemergent herbicide. |
| A-908292
A-908292 is a potent and selective acetyl-CoA carboxylase 2 (ACC2) inhibitor, with an IC50 of 38 nM. A-908292 can be used for the research of fatty acid metabolism. |
| CMS-121
CMS-121 is an orally active acetyl-CoA carboxylase 1 (ACC1) inhibitor. CMS-121 protects HT22 cells against ischemia and oxidative damage with EC50 values of 7 nM and 200 nM, respectively. |
| PF-05221304
PF-05221304 is an orally bioavailable, liver-targeted inhibitor of acetyl-CoA carboxylase (ACC), an enzyme that catalyzes the first step of adipogenesis ab initio (DNL). |
| MK-4074
MK-4074 is a liver-specific inhibitor of acetyl-CoA carboxylase ACC1 and ACC2 with IC50 values of approximately 3 nM. |
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