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

2009; Elsevier BV; Volume: 19; Issue: 6 Linguagem: Inglês

10.1016/j.bmcl.2009.01.084

1464-3405

Tjeerd Barf, Fredrik Lehmann, Kristin Hammer, Saba Haile, Eva Axén, Carmen Medina, J. Uppenberg, Stefan Svensson, L Rondahl, Thomas Lundbäck,

Neuropeptides and Animal Physiology

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.