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

• Published in: Chemical & pharmaceutical bulletin Vol. 61; no. 12; pp. 1239 - 1247
• Main Authors: Lim, Chae Jo, Choi, Jun Young, Lee, Byung Ho, Oh, Kwang-Seok, Yi, Kyu Yang
• Format: Journal Article
• Language: English; Japanese
• Published: TOKYO The Pharmaceutical Society of Japan 01.12.2013; Pharmaceutical Society of Japan; Pharmaceutical Soc Japan
• Subjects: Amides - chemistry; Amides - pharmacology; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Furans - chemistry; Furans - pharmacology; Humans; Hypothalamic Hormones - antagonists & inhibitors; Hypothalamic Hormones - metabolism; Life Sciences & Biomedicine; MCH-receptor 1 antagonist; melanin concentrating hormone (MCH); Melanins - antagonists & inhibitors; Melanins - metabolism; naphtho[1,2-b]furan-2-carboxamide; obesity; Pharmacology & Pharmacy; Physical Sciences; Pituitary Hormones - antagonists & inhibitors; Pituitary Hormones - metabolism; Recombinant Proteins - metabolism; Science & Technology; Structure-Activity Relationship; MCH-R1 ANTAGONISTS; RESISTANCE; melanin concentrating hormone (MCH); MICE; SKIN; naphtho[1,2-b]furan-2-carboxamide; SAR INVESTIGATIONS; MCH-receptor 1 antagonist; obesity; DISCOVERY
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.c13-00486

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 n M . This substance also displays good metabolic stability and it does not significantly inhibit cytochrome P450 (CYP450) enzymes. However, 10b has unacceptable oral bioavailability.