title: Design and synthesis of selective, dual fatty acid binding protein 4 and 5 inhibitors.
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.
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland. Electronic address: holger.kuehne@roche.com.
authors.forename: Holger
authors.initials: H
authors.lastname: Kühne
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Obst-Sander
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland.
authors.forename: Bernd
authors.initials: B
authors.lastname: Kuhn
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland.
authors.forename: Aurelia
authors.initials: A
authors.lastname: Conte
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland.
authors.forename: Simona M
authors.initials: SM
authors.lastname: Ceccarelli
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland.
authors.forename: Werner
authors.initials: W
authors.lastname: Neidhart
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland.
authors.forename: Markus G
authors.initials: MG
authors.lastname: Rudolph
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Ottaviani
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Gasser
authors.affiliation: Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA.
authors.forename: Sung-Sau
authors.initials: SS
authors.lastname: So
authors.affiliation: Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA.
authors.forename: Shirley
authors.initials: S
authors.lastname: Li
authors.affiliation: Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Gao
authors.affiliation: Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Myers
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015195:Drug Design; D050556:Fatty Acid-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051379:Mice; D018345:Mice, Knockout; D010599:Pharmacokinetics; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid
chemical_list: C493410:FABP4 protein, human; C493412:FABP5 protein, human; D050556:Fatty Acid-Binding Proteins
keywords: FABP4; FABP5; Quinoline derivatives; Structure-based design