ABSTRACT
Here we report the discovery and optimization of a series of bivalent bromodomain and extraterminal inhibitors. Starting with the observation of BRD4 activity of compounds from a previous program, the compounds were optimized for BRD4 potency and physical properties. The optimized compound from this campaign exhibited excellent pharmacokinetic profile and exhibited high potency in vitro and in vivo effecting c-Myc downregulation and tumor growth inhibition in xenograft studies. This compound was selected as the development candidate, AZD5153. The series showed enhanced potency as a result of bivalent binding and a clear correlation between BRD4 activity and cellular potency.
Subject(s)
Antineoplastic Agents/chemistry , Heterocyclic Compounds, 2-Ring/chemistry , Nuclear Proteins/antagonists & inhibitors , Piperazines/chemistry , Transcription Factors/antagonists & inhibitors , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Caco-2 Cells , Cell Cycle Proteins , Crystallography, X-Ray , Dogs , Female , Hepatocytes/drug effects , Hepatocytes/metabolism , Heterocyclic Compounds, 2-Ring/pharmacokinetics , Heterocyclic Compounds, 2-Ring/pharmacology , Heterografts , Humans , Mice, SCID , Neoplasm Transplantation , Piperazines/pharmacokinetics , Piperazines/pharmacology , Protein Conformation , Pyrazoles , Pyridazines , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Removal of the basic piperazine nitrogen atom, introduction of a solubilising end group and partial reduction of the triazolopyridazine moiety in the previously-described lead androgen receptor downregulator 6-[4-(4-cyanobenzyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (1) addressed hERG and physical property issues, and led to clinical candidate 6-(4-{4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (12), designated AZD3514, that is being evaluated in a Phase I clinical trial in patients with castrate-resistant prostate cancer.
