title: Discovery and synthesis of novel 4-aminopyrrolopyrimidine Tie-2 kinase inhibitors for the treatment of solid tumors.
abstract: The synthesis and biological evaluation of novel Tie-2 kinase inhibitors are presented. Based on the pyrrolopyrimidine chemotype, several new series are described, including the benzimidazole series by linking a benzimidazole to the C5-position of the 4-amino-pyrrolopyrimidine core and the ketophenyl series synthesized by incorporating a ketophenyl group to the C5-position. Medicinal chemistry efforts led to potent Tie-2 inhibitors. Compound 15, a ketophenyl pyrrolopyrimidine urea analog with improved physicochemical properties, demonstrated favorable in vitro attributes as well as dose responsive and robust oral tumor growth inhibition in animal models.
authors.affiliation: Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340, United States.
authors.forename: Joel T
authors.initials: JT
authors.lastname: Arcari
authors.forename: Jean S
authors.initials: JS
authors.lastname: Beebe
authors.forename: Martin A
authors.initials: MA
authors.lastname: Berliner
authors.forename: Vincent
authors.initials: V
authors.lastname: Bernardo
authors.forename: Merin
authors.initials: M
authors.lastname: Boehm
authors.forename: Gary V
authors.initials: GV
authors.lastname: Borzillo
authors.forename: Tracey
authors.initials: T
authors.lastname: Clark
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Cohen
authors.forename: Richard D
authors.initials: RD
authors.lastname: Connell
authors.forename: Heather N
authors.initials: HN
authors.lastname: Frost
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Gordon
authors.forename: William M
authors.initials: WM
authors.lastname: Hungerford
authors.forename: Shefali M
authors.initials: SM
authors.lastname: Kakar
authors.forename: Aaron
authors.initials: A
authors.lastname: Kanter
authors.forename: Nandell F
authors.initials: NF
authors.lastname: Keene
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Knauth
authors.forename: Susan D
authors.initials: SD
authors.lastname: Lagreca
authors.forename: Yong
authors.initials: Y
authors.lastname: Lu
authors.forename: Louis
authors.initials: L
authors.lastname: Martinez-Alsina
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Marx
authors.forename: Joel
authors.initials: J
authors.lastname: Morris
authors.forename: Nandini C
authors.initials: NC
authors.lastname: Patel
authors.forename: Doug
authors.initials: D
authors.lastname: Savage
authors.forename: Cathy I
authors.initials: CI
authors.lastname: Soderstrom
authors.forename: Carl
authors.initials: C
authors.lastname: Thompson
authors.forename: George
authors.initials: G
authors.lastname: Tkalcevic
authors.forename: Norma J
authors.initials: NJ
authors.lastname: Tom
authors.forename: Felix F
authors.initials: FF
authors.lastname: Vajdos
authors.forename: James J
authors.initials: JJ
authors.lastname: Valentine
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Vincent
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Wessel
authors.forename: Jinshan M
authors.initials: JM
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008297:Male; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: C584284:4-aminopyrrolopyrimidine; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D042787:Receptor, TIE-2