title: Naphthyridines as novel BET family bromodomain inhibitors.
abstract: Bromodomains (BRDs) are small protein domains found in a variety of proteins that recognize and bind to acetylated histone tails. This binding affects chromatin structure and facilitates the localisation of transcriptional complexes to specific genes, thereby regulating epigenetically controlled processes including gene transcription and mRNA elongation. Inhibitors of the bromodomain and extra-terminal (BET) proteins BRD2-4 and T, which prevent bromodomain binding to acetyl-modified histone tails, have shown therapeutic promise in several diseases. We report here the discovery of 1,5-naphthyridine derivatives as potent inhibitors of the BET bromodomain family with good cell activity and oral pharmacokinetic parameters. X-ray crystal structures of naphthyridine isomers have been solved and quantum mechanical calculations have been used to explain the higher affinity of the 1,5-isomer over the others. The best compounds were progressed in a mouse model of inflammation and exhibited dose-dependent anti-inflammatory pharmacology.
authors.affiliation: Centre de Recherches François Hyafil, GlaxoSmithKline R&D, 25 Avenue du Québec, 91140 Villebon-sur-Yvette (France); Current address: Institut de Recherches Servier, 11 Rue des Moulineaux, 92150 Suresnes (France). oliviermirguet@yahoo.fr.
authors.forename: Olivier
authors.initials: O
authors.lastname: Mirguet
authors.forename: Yann
authors.initials: Y
authors.lastname: Lamotte
authors.forename: Chun-Wa
authors.initials: CW
authors.lastname: Chung
authors.forename: Paul
authors.initials: P
authors.lastname: Bamborough
authors.forename: Delphine
authors.initials: D
authors.lastname: Delannée
authors.forename: Anne
authors.initials: A
authors.lastname: Bouillot
authors.forename: Françoise
authors.initials: F
authors.lastname: Gellibert
authors.forename: Gael
authors.initials: G
authors.lastname: Krysa
authors.forename: Antonia
authors.initials: A
authors.lastname: Lewis
authors.forename: Jason
authors.initials: J
authors.lastname: Witherington
authors.forename: Pascal
authors.initials: P
authors.lastname: Huet
authors.forename: Yann
authors.initials: Y
authors.lastname: Dudit
authors.forename: Lionel
authors.initials: L
authors.lastname: Trottet
authors.forename: Edwige
authors.initials: E
authors.lastname: Nicodeme
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D002868:Chromosomal Proteins, Non-Histone; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D015394:Molecular Structure; D009287:Naphthyridines / Q000737:chemistry / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000187:drug effects; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002868:Chromosomal Proteins, Non-Histone; D006657:Histones; D009287:Naphthyridines; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; C518475:BRDT protein, mouse; D000092468:Bromodomain Containing Proteins; C490844:Brd2 protein, mouse; C518476:Brd3 protein, mouse; C486694:Brd4 protein, mouse
keywords: BET family bromodomains inhibitors; epigenetic readers; inflammation; naphthyridines