N-Benzyl-indolo carboxylic acids: Design and synthesis of potent and selective adipocyte fatty-acid binding protein (A-FABP) inhibitors.
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.
Barf
Tjeerd
T
Department of Medicinal Chemistry, Biovitrum AB, Research, 112 76 Stockholm, Sweden.
Lehmann
Fredrik
F
Hammer
Kristin
K
Haile
Saba
S
Axen
Eva
E
Medina
Carmen
C
Uppenberg
Jonas
J
Svensson
Stefan
S
Rondahl
Lena
L
Lundbäck
Thomas
T
D017667:Adipocytes / Q000187:drug effects*; D000818:Animals; D001665:Binding Sites; D002264:Carboxylic Acids / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D050556:Fatty Acid-Binding Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008956:Models, Chemical; D015394:Molecular Structure; D013050:Spectrometry, Fluorescence / Q000379:methods
D002264:Carboxylic Acids; D050556:Fatty Acid-Binding Proteins