Evolution of the Synthesis of AMPK Activators for the Treatment of Diabetic Nephropathy: From Three Preclinical Candidates to the Investigational New Drug PF-06409577

Indole acids 1, 2, and 3 are potent 5′-adenosine monophosphate-activated
protein kinase
(AMPK) activators for the potential treatment of diabetic nephropathy.
Compounds 1–3 were scaled to supply
material for preclinical studies, and indole 3 was selected
for advancement to first-in-human clinical trials and scaled to kilogram
quantities. The progression of the synthesis strategy for these AMPK
activators is described, as routes were selected for efficient structure–activity
relationship generation and then improved for larger scales. The developed
sequences employed practical isolations of intermediates and APIs,
reproducible cross-coupling, hydrolysis, and other transformations,
and enhanced safety and purity profiles and led to the production
of 40–50 g of 1 and 2 and 2.4 kg
of 3. Multiple polymorphs of 3 were observed,
and conditions for the reproducible formation of crystalline material
suitable for clinical development were identified.