title: 5-((4-Aminopiperidin-1-yl)methyl)pyrrolotriazine dual inhibitors of EGFR and HER2 protein tyrosine kinases.
abstract: 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.
authors.affiliation: Department of Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492-1951, USA. harold.mastalerz@bms.com
authors.forename: Harold
authors.initials: H
authors.lastname: Mastalerz
authors.forename: Ming
authors.initials: M
authors.lastname: Chang
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Brian E
authors.initials: BE
authors.lastname: Fink
authors.forename: Ashvinikumar
authors.initials: A
authors.lastname: Gavai
authors.forename: Wen-Ching
authors.initials: WC
authors.lastname: Han
authors.forename: Walter
authors.initials: W
authors.lastname: Johnson
authors.forename: David
authors.initials: D
authors.lastname: Langley
authors.forename: Francis Y
authors.initials: FY
authors.lastname: Lee
authors.forename: Kenneth
authors.initials: K
authors.lastname: Leavitt
authors.forename: Punit
authors.initials: P
authors.lastname: Marathe
authors.forename: Derek
authors.initials: D
authors.lastname: Norris
authors.forename: Simone
authors.initials: S
authors.lastname: Oppenheimer
authors.forename: Bogdan
authors.initials: B
authors.lastname: Sleczka
authors.forename: James
authors.initials: J
authors.lastname: Tarrant
authors.forename: John S
authors.initials: JS
authors.lastname: Tokarski
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Vite
authors.forename: Dolatrai M
authors.initials: DM
authors.lastname: Vyas
authors.forename: Henry
authors.initials: H
authors.lastname: Wong
authors.forename: Tai W
authors.initials: TW
authors.lastname: Wong
authors.forename: Hongjian
authors.initials: H
authors.lastname: Zhang
authors.forename: Guifen
authors.initials: G
authors.lastname: Zhang
mesh_terms: 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
chemical_list: D000255:Adenosine Triphosphate; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D010880:Piperidines; D011758:Pyrroles; D018719:Erb-b2 Receptor Tyrosine Kinases; D014227:Triazines