title: Design, synthesis, and evaluation of orally active 4-(2,4-difluoro-5-(methoxycarbamoyl)phenylamino)pyrrolo[2,1-f][1,2,4]triazines as dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 inhibitors.
abstract: A series of substituted 4-(2,4-difluoro-5-(methoxycarbamoyl)phenylamino)pyrrolo[2,1-f][1,2,4]triazines was identified as potent and selective inhibitors of the tyrosine kinase activity of the growth factor receptors VEGFR-2 (Flk-1, KDR) and FGFR-1. The enzyme kinetics associated with the VEGFR-2 inhibition of compound 50 (K(i) = 52 +/- 3 nM) confirmed that the pyrrolo[2,1-f][1,2,4]triazine analogues are competitive with ATP. Several analogues demonstrated low-nanomolar inhibition of VEGF- and FGF-dependent human umbilical vein endothelial cell (HUVEC) proliferation. Replacement of the C6-ester substituent of the pyrrolo[2,1-f][1,2,4]triazine core with heterocyclic bioisosteres, such as substituted 1,3,5-oxadiazoles, afforded compounds with excellent oral bioavailability in mice (i.e., 50 F(po) = 79%). Significant antitumor efficacy was observed with compounds 44, 49, and 50 against established L2987 human lung carcinoma xenografts implanted in athymic mice. A full account of the synthesis, structure-activity relationships, pharmacology, and pharmacokinetic properties of analogues within the series is presented.
authors.affiliation: Department of Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA. robert.borzilleri@bms.com
authors.forename: Robert M
authors.initials: RM
authors.lastname: Borzilleri
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zheng
authors.forename: Ligang
authors.initials: L
authors.lastname: Qian
authors.forename: Christopher
authors.initials: C
authors.lastname: Ellis
authors.forename: Zhen-wei
authors.initials: ZW
authors.lastname: Cai
authors.forename: Barri S
authors.initials: BS
authors.lastname: Wautlet
authors.forename: Steve
authors.initials: S
authors.lastname: Mortillo
authors.forename: Robert
authors.initials: R
authors.lastname: Jeyaseelan
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Kukral
authors.forename: Aberra
authors.initials: A
authors.lastname: Fura
authors.forename: Amrita
authors.initials: A
authors.lastname: Kamath
authors.forename: Viral
authors.initials: V
authors.lastname: Vyas
authors.forename: John S
authors.initials: JS
authors.lastname: Tokarski
authors.forename: Joel C
authors.initials: JC
authors.lastname: Barrish
authors.forename: John T
authors.initials: JT
authors.lastname: Hunt
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Lombardo
authors.forename: Joseph
authors.initials: J
authors.lastname: Fargnoli
authors.forename: Rajeev S
authors.initials: RS
authors.lastname: Bhide
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: C501754:2,4-difluoro-5-(5-isopropyl-6-(5-(methylsulfonylmethyl)-1,3,4-oxadiazol-2-yl)pyrrolo(2,1-f)(1,2,4)triazin-4-ylamino)-N-methoxybenzamide; C501755:5-(6-(5-(difluoro(methylsulfonyl)methyl)-1,3,4-oxadiazol-2-yl)-5-isopropylpyrrolo(2,1-f)(1,2,4)triazin-4-ylamino)-2,4-difluoro-N-methoxybenzamide; C501753:5-(6-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-5-isopropylpyrrolo(2,1-f)(1,2,4)triazin-4-ylamino)-2,4-difluoro-N-methoxybenzamide; D000970:Antineoplastic Agents; D001798:Blood Proteins; D006877:Hydroxamic Acids; D010069:Oxadiazoles; D011758:Pyrroles; D017468:Receptors, Fibroblast Growth Factor; D014227:Triazines; C496348:FGFR1 protein, human; C496349:Fgfr1 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D040301:Vascular Endothelial Growth Factor Receptor-2