Design, synthesis, and pharmacological evaluation of N-bicyclo-5-chloro-1H-indole-2-carboxamide derivatives as potent glycogen phosphorylase inhibitors

• Published in: Bioorganic & medicinal chemistry Vol. 16; no. 23; pp. 10001 - 10012
• Main Authors: Onda, Kenichi, Shiraki, Ryota, Ogiyama, Takashi, Yokoyama, Kazuhiro, Momose, Kazuhiro, Katayama, Naoko, Orita, Masaya, Yamaguchi, Tomohiko, Furutani, Masako, Hamada, Noritaka, Takeuchi, Makoto, Okada, Minoru, Ohta, Mitsuaki, Tsukamoto, Shin-ichi
• Format: Journal Article
• Language: English
• Published: England 01.12.2008
• Subjects: Administration, Oral; Animals; Benzamides - chemical synthesis; Benzamides - chemistry; Benzamides - pharmacology; Cells, Cultured; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Glucose; Glycogen Phosphorylase - antagonists & inhibitors; Hepatocytes - drug effects; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Inhibitory Concentration 50; Male; Mice; Mice, Obese; Molecular Structure; Rats; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2008.10.021

As a result of the various N-bicyclo-5-chloro-1H-indole-2-carboxamide derivatives with a hydroxy moiety synthesized in an effort to discover novel glycogen phosphorylase (GP) inhibitors, 5-chloro-N-(5-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-indole-2-carboxamide (5b) was found to have potent inhibitory activity. The introduction of fluorine atoms both at a position adjacent to the hydroxy group and in the central benzene moiety lead to the optically active derivative 5-chloro-N-[(5R)-1,3,6,6-tetrafluoro-5-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1H-indole-2-carboxamide (25e(alpha), which was the most potent compound in this series (IC(50)=0.020microM). This compound inhibited glucagon-induced glucose output in cultured primary hepatocytes with an IC(50) value of 0.69microM, and showed oral hypoglycemic activity in diabetic db/db mice at 10mg/kg. Compound 25e(alpha) also had an excellent pharmacokinetic profile, with high oral bioavailability and a long plasma half-life, in male SD rats. The binding mode of 25e(alpha) to this molecule and the role of fluorine atoms in that binding were speculated in an enzyme docking study.