PF-04991532 is an effective, hepatoselective glucokinase activator. It has EC50s of 80 and 100 nM in human and rat, respectively.

GK (human):（EC50）80 nM, GK (rat):100 nM（EC50）

PF-04991532 is a Phase 2 clinical candidate. PF-04991532 reduces the production of glucose from 1-[14C]-lactate in a dose-dependent manner (EC50?=0.626 μM). PF-04991532 enhances the expression of G6Pase compare to cells treated only with 100 nM glucagon, in isolated rat hepatocytes. The greatest increase in G6Pase mRNA expression is in the presence of 25 mM glucose, 100 nM glucagon, and PF-04991532. Mechanistic experiments conducted in freshly isolated primary rat hepatocytes treated for 1 hour with PF-04991532 display increased 2-[14C]-deoxyglucose uptake (EC50?=1.261 μM) and increased glucose oxidation (EC50=5.769 μM) [1].

PF-04991532 (a single dose) enhances the glucose infusion rate in order to maintain hyperglycemia. PF-04991532 (in rats) treatment, there is increased expression of lipogenic gene expression such as acetyl-CoA carboxylase (ACC), ATP citrate lyase (ACLY), and fatty acid synthase (FAS). Despite the elevations in plasma triglycerides, hepatic triglycerides in rats dosed with 19 days of PF-04991532 are identical to vehicle-treated GK rats. Identical hepatic lipid concentrations are observed between vehicle and rats dosed with PF-04991532 (Vehicle: 9.89±0.31; PF-04991532 100 mg/kg: 9.91±0.31), in an additional cohort treated for 28 days [1].