PF-05175157

Research use only, not for human use.

PF-05175157 (PF-5175157) is a potennt Acetyl-CoA carboxylase (ACC) inhibitor with IC50 of 27 and 33 nM for hAAC1 and hACC2, respectively.

PF-05175157 (PF-5175157) is a potennt Acetyl-CoA carboxylase (ACC) inhibitor with IC50 of 27 and 33 nM for hAAC1 and hACC2, respectively; shows concentration-dependent reductions in both skeletal muscle and liver malonyl-CoA with EC50 of 870 and 540 nM after 1 h following an acute oral dose in rats; demonstrates significant potential for the treatment of type 2 diabetes mellitus (T2DM).Diabetes Phase 2 Discontinued(In Vitro):PF-05175157 is broad spectrum acetyl-CoA carboxylase (ACC) inhibitor with IC50s of 27.0±2.7, 33.0±4.1, 23.5±1.1 and 50.4±2.6 nM for ACC1 (human), ACC2 (human), ACC1 (rat) and ACC2 (rat), respectively. The in vitro metabolism of PF-05175157 (Compound 9) is evaluated in microsomes from rat, dog, and human hepatocytes. 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.

——

——

PF05175157 | PF-5175157

Metabolic Enzyme/Protease

ACC

ACC

Metabolic Disease

Diabetes

1301214-47-0

405.49

C23H27N5O2

>98% (HPLC)

DMSO : 30 mg/mL. 73.98 mM

O=C1CC2(CCN(C(C3=CC=C4N=C(C)NC4=C3)=O)CC2)CC5=C1N(C(C)C)N=C5

1,4-Dihydro-1'-[(2-methyl-1H-benzimidazol-6-yl)carbonyl]-1-(1-methylethyl)spiro[5H-indazole-5,4'-piperidin]-7(6H)-one

(-20℃)

With Ice Pack

≥ 2 years