Optimization of Pharmacokinetic and In Vitro Safety Profile of a Series of Pyridine Diamide Indirect AMPK Activators

A set
of focused analogues have been generated around a lead indirect
adenosine monophosphate-activated kinase (AMPK) activator to improve
the rat clearance of the molecule. Analogues were focused on inhibiting
amide hydrolysis by the strategic placement of substituents that increased
the steric environment about the secondary amide bond between 4-aminopiperidine
and pyridine-5-carboxylic acid. It was found that placing substituents
at position 3 of the piperidine ring and position 4 of the pyridine
could all improve clearance without significantly impacting on-target
potency. Notably, trans-3-fluoropiperidine 32 reduced rat clearance from above liver blood flow to 19
mL/min/kg and improved the hERG profile by attenuating the basicity
of the piperidine moiety. Oral dosing of 32 activated
AMPK in mouse liver and after 2 weeks of dosing improved glucose handling
in a db/db mouse model of Type II diabetes as well as lowering fasted
glucose and insulin levels.