Synthesis of novel bicyclo[4.1.0]heptane and bicyclo[3.1.0]hexane derivatives as melanin-concentrating hormone receptor R1 antagonists

To address the hERG liability of MCHR1 antagonists such as 1 and 2, new analogs such as 4 and 5 that incorporated a polar heteroaryl group were designed and synthesized. Biological evaluation confirmed that these new analogs retained MCH R1 activity with greatly attenuated hERG liabilities as indicated in the Rb efflux assay.

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