Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 4. Exploration of a novel binding pocket.

Structure–activity relationship investigations conducted at the 5-position of the N-pyridine ring of a series of N-arylsulfonyl-N′-2-pyridinyl- piperazinesled to the identification of a novel bis-pyridinyl piperazinesulfonamide (51) that was a potent disruptor of the glucokinase– glucokinase regulatory protein(GK–GKRP) interaction. Analysis of the X-ray cocrystalof compound 51 bound to hGKRP revealed that the 3-pyridine ring moiety occupied a previously unexplored binding pocket within the protein. Key features of this new binding mode included forming favorable contacts with the top face of the Ala27-Val28-Pro29 (“shelf region”) as well as an edge-to-face interaction with the Tyr24 side chain. Compound 51 was potent in both biochemical and cellular assays (IC50 = 0.005 μM and EC50 = 0.205 μM, respectively) and exhibited acceptable pharmacokinetic properties for in vivo evaluation. When administered to db/db mice (100 mg/kg, po), compound 51 demonstrated a robust pharmacodynamic effect and significantly...