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).
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.
Wissner
Allan
A
Chemical Sciences, Oncology and Immunoinflammatory Research, Wyeth Research, 401 North Middletown Road, Pearl River, New York 10965, USA. wissnea@wyeth.com
Overbeek
Elsebe
E
Reich
Marvin F
MF
Floyd
M Brawner
MB
Johnson
Bernard D
BD
Mamuya
Nellie
N
Rosfjord
Edward C
EC
Discafani
Carolyn
C
Davis
Rachel
R
Shi
Xiaoqing
X
Rabindran
Sridhar K
SK
Gruber
Brian C
BC
Ye
Fei
F
Hallett
William A
WA
Nilakantan
Ramaswamy
R
Shen
Ru
R
Wang
Yu-Fen
YF
Greenberger
Lee M
LM
Tsou
Hwei-Ru
HR
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
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