hERG Optimization of Benzofuro−Pyridine and Pyrazino−Indole Derivatives as MCHR1 Antagonists

Obesity is a global epidemic associated with multiple severe diseases. Several pharmacotherapies have been investigated including the antagonists of melanin concentrating hormone receptor 1 (MCHR1). The design, synthesis, and biological studies of novel MCHR1 antagonists based on benzofuro−pyridine and pyrazino−indole scaffold was performed. We confirmed that fine‐tuning lipophilicity and basic pKa by modifying the benzyl group and introducing different substituents on the aliphatic nitrogen sidechain decreases both hERG inhibition and metabolic clearance. We have succeeded to develop excellent in vitro parameters in the case of compounds 17 (4‐[(5‐chloropyridin‐2‐yl)methoxy]‐1‐[4‐(2‐hydroxyethyl)‐8‐oxa‐4‐azatricyclo[7.4.0.02,7]trideca‐1(13),2(7),9,11‐tetraen‐11‐yl]‐1,2‐dihydropyridin‐2‐one monohydrochloride) and 23 g (4‐[(5‐chloropyridin‐2‐yl)methoxy]‐1‐(1,2,3,4‐tetrahydropyrazino[1,2‐a]indol‐8‐yl)pyridin‐2(1H)‐one monohydrochloride), which can be considered as valuable tools for further pharmacological investigation. Healthier heart: Melanin concentrating hormone receptor 1 (MCHR1) antagonists containing benzofuro−pyridine or pyrazino−indole scaffolds have been identified. Fine‐tuning the lipophilicity and amine basicity provided compounds 17 and 23 g with both decreased hERG inhibition and metabolic clearance.