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Inhibition of Hypoxia‐Induced Gene Transcription by Substituted Pyrazolyl Oxadiazoles: Initial Lead Generation and Structure–Activity Relationships
Author(s) -
Härter Michael,
Thierauch KarlHeinz,
Boyer Stephen,
Bhargava Ajay,
Ellinghaus Peter,
Beck Hartmut,
GreschatSchade Susanne,
HessStumpp Holger,
Unterschemmann Kerstin
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300357
Subject(s) - transactivation , hypoxia (environmental) , lead compound , chemistry , transcription factor , cancer research , potency , pharmacology , transcription (linguistics) , a549 cell , apoptosis , gene , microbiology and biotechnology , in vitro , biochemistry , biology , oxygen , linguistics , philosophy , organic chemistry
The transcription factors hypoxia‐inducible factor‐1 and ‐2 (HIF‐1 and HIF‐2) orchestrate a multitude of processes that allow tumor cells to survive under conditions of low oxygen and nutrients, and that lead to resistance to some apoptotic pathways and facilitate invasion and metastasis. Therefore, inhibition of transactivation by HIF has become an attractive target in cancer research. Herein we present the results of a cell‐based screening approach that led to the discovery of substituted 1 H ‐pyrazole‐3‐carboxamides. Chemical optimization of the hit class with respect to potency and metabolic stability is described; it resulted in novel 5‐(1 H ‐pyrazol‐3‐yl)‐1,2,4‐oxadiazoles that inhibit the hypoxia‐induced accumulation of HIF‐1α and HIF‐2α. The HIF inhibitory potency in the screening cell system was improved from IC 50 190 to 0.7 n M , and significant parts of the SAR are disclosed. For a key compound, the ability to suppress the hypoxia‐induced expression of HIF target genes was studied in A549 human lung adenocarcinoma cells. The same compound shows a favorable pharmacokinetic profile in rats after i.v. and p.o. administration.