2. Academic Validation
  3. Design and synthesis of selective, dual fatty acid binding protein 4 and 5 inhibitors

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

Affiliations

  • 1 Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland. Electronic address: holger.kuehne@roche.com.
  • 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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