N-Benzyl-indolo carboxylic acids: Design and synthesis of potent and selective adipocyte fatty-acid binding protein (A-FABP) inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2009-03, Vol.19 (6), p.1745-1748
• Main Authors: Barf, Tjeerd, Lehmann, Fredrik, Hammer, Kristin, Haile, Saba, Axen, Eva, Medina, Carmen, Uppenberg, Jonas, Svensson, Stefan, Rondahl, Lena, Lundbäck, Thomas
• Format: Article
• Language: English
• Subjects: Adipocytes - drug effects; Animals; Binding Sites; Biological and medical sciences; Carboxylic Acids - chemistry; Chemistry, Pharmaceutical - methods; Crystallography, X-Ray - methods; Drug Design; Fatty Acid-Binding Proteins - antagonists & inhibitors; General and cellular metabolism. Vitamins; Humans; Inhibitory Concentration 50; Macrophages - metabolism; Medical sciences; Mice; Models, Chemical; Molecular Structure; Pharmacology. Drug treatments; Spectrometry, Fluorescence - methods
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.01.084

A novel class of hexahydrocyclohepta[b]indole-based A-FABP inhibitors have been synthesized and evaluated. The potency, selectivity profile, and structure–activity relationship trends of this class of compounds are discussed. Small molecule inhibitors of adipocyte fatty-acid binding protein (A-FABP) have gained renewed interest following the recent publication of pharmacologically beneficial effects of such inhibitors. Despite the potential utility of selective A-FABP inhibitors within the fields of metabolic disease, inflammation and atherosclerosis, there are few examples of useful A-FABP inhibitors in the public domain. Herein, we describe the optimization of N-benzyl-tetrahydrocarbazole derivatives through the use of co-crystal structure guided medicinal chemistry efforts. This led to the identification of a potent and selective class of A-FABP inhibitors as illustrated by N-benzyl-hexahydrocyclohepta[ b]indole 30.