title: Synthesis and structure-activity relationships of 6,7-disubstituted 4-anilinoquinoline-3-carbonitriles. The design of an orally active, irreversible inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor-2 (HER-2).
abstract: A series of of 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile derivatives that function as irreversible inhibitors of EGFR and HER-2 kinases have been prepared. These inhibitors have, at the 6-position, butynamide, crotonamide, and methacrylamide Michael acceptors bearing water-solublilizing substituents. These compounds were prepared by acylation of 6-amino-4-(arylamino)quinoline-3-carbonitriles with unsaturated acid chlorides or mixed anhydrides. We performed competitive reactivity studies showing that attaching a dialkylamino group onto the end of the Michael acceptor results in compounds with greater reactivity due to intramolecular catalysis of the Michael addition. This, along with improved water-solubility results in compounds with enhanced biological properties. We present molecular modeling results consistent with the proposed mechanism of inhibition. One compound, 5 (EKB-569), which shows excellent oral in vivo activity, was selected for further studies and is currently in phase I clinical trials for the treatment of cancer.
authors.affiliation: Chemical Sciences, Oncology and Immunoinflammatory Research, Wyeth Research, 401 North Middletown Road, Pearl River, New York 10965, USA. wissnea@wyeth.com
authors.forename: Allan
authors.initials: A
authors.lastname: Wissner
authors.forename: Elsebe
authors.initials: E
authors.lastname: Overbeek
authors.forename: Marvin F
authors.initials: MF
authors.lastname: Reich
authors.forename: M Brawner
authors.initials: MB
authors.lastname: Floyd
authors.forename: Bernard D
authors.initials: BD
authors.lastname: Johnson
authors.forename: Nellie
authors.initials: N
authors.lastname: Mamuya
authors.forename: Edward C
authors.initials: EC
authors.lastname: Rosfjord
authors.forename: Carolyn
authors.initials: C
authors.lastname: Discafani
authors.forename: Rachel
authors.initials: R
authors.lastname: Davis
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Shi
authors.forename: Sridhar K
authors.initials: SK
authors.lastname: Rabindran
authors.forename: Brian C
authors.initials: BC
authors.lastname: Gruber
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.forename: William A
authors.initials: WA
authors.lastname: Hallett
authors.forename: Ramaswamy
authors.initials: R
authors.lastname: Nilakantan
authors.forename: Ru
authors.initials: R
authors.lastname: Shen
authors.forename: Yu-Fen
authors.initials: YF
authors.lastname: Wang
authors.forename: Lee M
authors.initials: LM
authors.lastname: Greenberger
authors.forename: Hwei-Ru
authors.initials: HR
authors.lastname: Tsou
mesh_terms: D000284:Administration, Oral; D000634:Aminoquinolines; D000814:Aniline Compounds; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005978:Glutathione / Q000037:antagonists & inhibitors; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009930:Organic Chemicals; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000634:Aminoquinolines; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D005978:Glutathione; D009930:Organic Chemicals; D018719:Erb-b2 Receptor Tyrosine Kinases; C413879:EKB 569