5-((4-Aminopiperidin-1-yl)methyl)pyrrolotriazine dual inhibitors of EGFR and HER2 protein tyrosine kinases.
Pyrrolotriazine dual EGFR/HER2 kinase inhibitors with a 5-((4-aminopiperidin-1-yl)methyl) solubilizing group were found to be superior to analogs with previously reported C-5 solubilizing groups. New synthetic methodology was developed for the parallel synthesis of C-4 analogs with the new solubilizing group. Interesting new leads were evaluated in tumor xenograft models and the C-4 aminofluorobenzylindazole, 1c, was found to exhibit the best antitumor activity. It is hypothesized that this solubilizing group extends into the ribose-phosphate portion of the ATP binding pocket and enhances the binding affinity of the inhibitor.
Mastalerz
Harold
H
Department of Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492-1951, USA. harold.mastalerz@bms.com
Chang
Ming
M
Chen
Ping
P
Fink
Brian E
BE
Gavai
Ashvinikumar
A
Han
Wen-Ching
WC
Johnson
Walter
W
Langley
David
D
Lee
Francis Y
FY
Leavitt
Kenneth
K
Marathe
Punit
P
Norris
Derek
D
Oppenheimer
Simone
S
Sleczka
Bogdan
B
Tarrant
James
J
Tokarski
John S
JS
Vite
Gregory D
GD
Vyas
Dolatrai M
DM
Wong
Henry
H
Wong
Tai W
TW
Zhang
Hongjian
H
Zhang
Guifen
G
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D007313:Insecta; D008956:Models, Chemical; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry*; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000255:Adenosine Triphosphate; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D010880:Piperidines; D011758:Pyrroles; D018719:Erb-b2 Receptor Tyrosine Kinases; D014227:Triazines