Synthesis and Structure–Activity Relationship of Naphtho[1,2-b]furan-2-carboxamide Derivatives as Melanin Concentrating Hormone Receptor 1 Antagonists

Abstract

The discovery that novel naphtho[1,2-b]furan-2-carboxamides containing linked piperidinylphenylacetamide groups serve as melanin concentrating hormone receptor 1 (MCH-R1) antagonists is described. An extensive structure–activity relationship (SAR) study, probing members of this family that contain a variety of aryl and heteroaryl groups at C-5 of the naphtho[1,2-b]furan-2-carboxamide skeleton and having different chain linker lengths, led to the identification of the 5-(4-pyridinyl) substituted analog 10b as a highly potent MCH-R1 antagonist with an IC₅₀ value of 3 nM. This substance also displays good metabolic stability and it does not significantly inhibit cytochrome P450 (CYP450) enzymes. However, 10b has unacceptable oral bioavailability.