Design and synthesis of selective, dual fatty acid binding protein 4 and 5 inhibitors

  • Bioorg Med Chem Lett. 2016 Oct 15;26(20):5092-5097. doi: 10.1016/j.bmcl.2016.08.071.
Holger Kühne  1 ,  Ulrike Obst-Sander  2 ,  Bernd Kuhn  2 ,  Aurelia Conte  2 ,  Simona M Ceccarelli  2 ,  Werner Neidhart  2 ,  Markus G Rudolph  2 ,  Giorgio Ottaviani  2 ,  Rodolfo Gasser  2 ,  Sung-Sau So  3 ,  Shirley Li  3 ,  Xiaolei Zhang  3 ,  Lin Gao  3 ,  Michael Myers  3
Affiliations
  • 1. Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland. Electronic address: [email protected].
  • 2. Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland.
  • 3. Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA.
PMID: 27658368 DOI: 10.1016/j.bmcl.2016.08.071
Abstract

Dual inhibition of fatty acid binding proteins 4 and 5 (FABP4 and FABP5) is expected to provide beneficial effects on a number of metabolic parameters such as Insulin sensitivity and blood glucose levels and should protect against atherosclerosis. Starting from a FABP4 selective focused screening hit, biostructure information was used to modulate the selectivity profile in the desired way and to design potent dual FABP4/5 inhibitors with good selectivity against FABP3. With very good pharmacokinetic properties and no major safety alerts, compound 12 was identified as a suitable tool compound for further in vivo investigations.

Keywords
FABP4; FABP5; Quinoline derivatives; Structure-based design.
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