Optimizing the Benefit/Risk of Acetyl-CoA Carboxylase Inhibitors through Liver Targeting

Preclinical
and clinical data suggest that acetyl-CoA carboxylase
(ACC) inhibitors have the potential to rebalance disordered lipid
metabolism, leading to improvements in nonalcoholic steatohepatitis
(NASH). Consistent with these observations, first-in-human clinical
trials with our ACC inhibitor PF-05175157 led to robust reduction
of de novo lipogenesis (DNL), albeit with concomitant reductions in
platelet count, which were attributed to the inhibition of fatty acid
synthesis within bone marrow. Herein, we describe the design, synthesis,
and evaluation of carboxylic acid-based ACC inhibitors with organic
anion transporting polypeptide (OATP) substrate properties, which
facilitated selective distribution of the compounds at the therapeutic
site of action (liver) relative to the periphery. These efforts led
to the discovery of clinical candidate PF-05221304 (12), which selectively inhibits liver DNL in animals, while demonstrating
considerable safety margins against platelet reduction in a nonhuman
primate model.