Optimization of Metabolic and Renal Clearance in a Series of Indole Acid Direct Activators of 5′-Adenosine Monophosphate-Activated Protein Kinase (AMPK)

Optimization
of the pharmacokinetic (PK) properties of a series
of activators of adenosine monophosphate-activated protein kinase
(AMPK) is described. Derivatives of the previously described 5-aryl-indole-3-carboxylic
acid clinical candidate (1) were examined with the goal
of reducing glucuronidation rate and minimizing renal excretion. Compounds 10 (PF-06679142) and 14 (PF-06685249) exhibited
robust activation of AMPK in rat kidneys as well as desirable oral
absorption, low plasma clearance, and negligible renal clearance in
preclinical species. A correlation of in vivo renal clearance in rats
with in vitro uptake by human and rat renal organic anion transporters
(human OAT/rat Oat) was identified. Variation of polar functional
groups was critical to mitigate active renal clearance mediated by
the Oat3 transporter. Modification of either the 6-chloroindole core
to a 4,6-difluoroindole or the 5-phenyl substituent to a substituted
5-(3-pyridyl) group provided improved metabolic stability while minimizing
propensity for active transport by OAT3.