Acetyl-CoA carboxylase exists in two tissue-specific isoforms, and PF-05175157 targets both with comparable potency – IC50 of 27 nM for ACC1 and 33 nM for ACC2. The compound originated from a Pfizer medicinal chemistry program focused on metabolic disease and reached Phase I clinical evaluation for type 2 diabetes. PF-05175157 molecular weight is 405.49 g/mol; the PF-05175157 molecular structure centers on a spiro-fused indazole-piperidine framework decorated with a benzimidazole-carbonyl moiety and an isopropyl group (CAS 1301214-47-0). The free base dissolves readily in DMSO, making it suitable for standard cell-based and biochemical assay formats.
Application of PF-05175157
ACC occupies the rate-controlling position in fatty acid biosynthesis by generating malonyl-CoA – both the direct substrate for chain elongation and the endogenous brake on mitochondrial fat import via CPT-1. Blocking both isoforms simultaneously with PF-05175157 structure creates a dual metabolic shift: reduced lipogenic output in the liver and accelerated fatty acid entry into the mitochondrial matrix in muscle. Beyond metabolic disease, the compound has found application in virology – flavivirus replication depends on host lipid synthesis – and in cancer biology, where DNL supports tumor cell proliferation.
In Vitro
Enzyme inhibition profiling across species places PF-05175157 among the most potent dual ACC inhibitors characterized to date: IC50 values of 27.0 nM and 33.0 nM for human ACC1 and ACC2, shifting only modestly to 23.5 nM and 50.4 nM for the rat orthologs. The narrow interspecies gap in potency matters practically – it means that data generated in rodent biochemical assays can be interpreted alongside human enzyme data without significant correction for species differences.
In Vivo
Administered orally at 3 mg/kg, PF-05175157 achieved bioavailability of 40% in rats and 54% in dogs, values consistent with low hepatic clearance and adequate gastrointestinal absorption. In lean rats, a single dose measurably reduced malonyl-CoA concentrations in both liver and skeletal muscle within one hour, with a corresponding shift in whole-body respiratory exchange ratio toward greater fat utilization. Phase I data in healthy volunteers confirmed the same mechanistic footprint: suppressed DNL and increased fatty acid oxidation at the whole-body level. An unanticipated reduction in platelet count – traced to ACC inhibition within bone marrow progenitor cells – defined the primary pharmacodynamic liability.
Biochemical and Physiological Actions
The reaction catalyzed by ACC – ATP-dependent carboxylation of acetyl-CoA – is irreversible under physiological conditions, which makes it a particularly effective control point for regulating carbon flux into lipid synthesis. The PF-05175157 chemical structure targets the biotin carboxylase active site, sterically obstructing the binding of bicarbonate and preventing phosphoryl transfer. Isoform selectivity between ACC1 and ACC2 is difficult to achieve because the two enzymes share nearly identical catalytic domains; a dual inhibitor therefore avoids the interpretive complication of incomplete pathway suppression that arises when only one isoform is blocked.
Features and Benefits of PF-05175157
What sets PF-05175157 apart within the ACC inhibitor class is the depth of its documented profile: matched potency against both human and rodent isoforms, confirmed in vivo target engagement across multiple species, and pharmacodynamic validation in human Phase I studies with quantified DNL endpoints. That combination is rare among tool compounds in lipid metabolism research and makes PF-05175157 a practical reference standard for laboratories benchmarking new ACC inhibitors or probing the metabolic dependencies of disease models.
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