2,7-disubstituted-pyrrolo[2,1-f][1,2,4]triazines: new variant of an old template and application to the discovery of anaplastic lymphoma kinase (ALK) inhibitors with in vivo antitumor activity

Gregory R Ott; Gregory J Wells; Tho V Thieu; Matthew R Quail; Joseph G Lisko; Eugen F Mesaros; Diane E Gingrich; Arup K Ghose; Weihua Wan; Lihui Lu; Mangeng Cheng; Mark S Albom; Thelma S Angeles; Zeqi Huang; Lisa D Aimone; Mark A Ator; Bruce A Ruggeri; Bruce D Dorsey

doi:10.1021/jm200758k

2,7-disubstituted-pyrrolo[2,1-f][1,2,4]triazines: new variant of an old template and application to the discovery of anaplastic lymphoma kinase (ALK) inhibitors with in vivo antitumor activity

J Med Chem. 2011 Sep 22;54(18):6328-41. doi: 10.1021/jm200758k. Epub 2011 Aug 22.

Authors

Gregory R Ott¹, Gregory J Wells, Tho V Thieu, Matthew R Quail, Joseph G Lisko, Eugen F Mesaros, Diane E Gingrich, Arup K Ghose, Weihua Wan, Lihui Lu, Mangeng Cheng, Mark S Albom, Thelma S Angeles, Zeqi Huang, Lisa D Aimone, Mark A Ator, Bruce A Ruggeri, Bruce D Dorsey

Affiliation

¹ Worldwide Discovery Research, Cephalon, Inc., West Chester, Pennsylvania 19380, USA. gott@cephalon.com

PMID: 21859094
DOI: 10.1021/jm200758k

Abstract

A novel 2,7-disubstituted-pyrrolo[2,1-f][1,2,4]triazine scaffold has been designed as a new kinase inhibitor platform mimicking the bioactive conformation of the well-known diaminopyrimidine motif. The design, synthesis, and validation of this new pyrrolo[2,1-f][1,2,4]triazine scaffold will be described for inhibitors of anaplastic lymphoma kinase (ALK). Importantly, incorporation of appropriate potency and selectivity determinants has led to the discovery of several advanced leads that were orally efficacious in animal models of anaplastic large cell lymphoma (ALCL). A lead inhibitor (30) displaying superior efficacy was identified and in depth in vitro/in vivo characterization will be presented.

MeSH terms

Anaplastic Lymphoma Kinase
Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology
Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
Bridged Bicyclo Compounds, Heterocyclic / pharmacokinetics
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
Cell Line, Tumor
Cell Membrane Permeability
Drug Screening Assays, Antitumor
Humans
In Vitro Techniques
Lymphoma, Large-Cell, Anaplastic / drug therapy
Mice
Mice, SCID
Microsomes, Liver / metabolism
Models, Molecular
Neoplasm Transplantation
Pyrroles / chemical synthesis*
Pyrroles / pharmacokinetics
Pyrroles / pharmacology
Rats
Rats, Sprague-Dawley
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Structure-Activity Relationship
Sulfonamides / chemical synthesis*
Sulfonamides / pharmacokinetics
Sulfonamides / pharmacology
Transplantation, Heterologous
Triazines / chemical synthesis*
Triazines / pharmacokinetics
Triazines / pharmacology

Substances

Antineoplastic Agents
Bridged Bicyclo Compounds, Heterocyclic
N-(2-(2-(4-(4-(2-hydroxypropyl)piperazin-1-yl)-2-methoxyphenylamino)pyrrolo(2,1-f)(1,2,4)triazin-7-yl)phenyl)-N-methylmethanesulfonamide
Pyrroles
Sulfonamides
Triazines
ALK protein, human
Alk protein, mouse
Alk protein, rat
Anaplastic Lymphoma Kinase
Receptor Protein-Tyrosine Kinases