Optimization of a Series of Bivalent Triazolopyridazine Based Bromodomain and Extraterminal Inhibitors: The Discovery of (3R)-4-[2-[4-[1-(3-Methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-4-piperidyl]phenoxy]ethyl]-1,3-dimethyl-piperazin-2-one (AZD5153)
| Autor: | Joe Patel, Mark A. Graham, Maureen Hattersley, Stephen Stokes, David Whittaker, Carr Gregory Richard, David Whalley, Edwin Clark, Craig A. Roberts, Gail L. Wrigley, Alfred A. Rabow, Graeme Walker, Christopher R. Jones, Natalie Stratton, Michael J. Waring, Rowena Callis, Lyman Feron, Robert Hugh Bradbury, Steve C. Glossop, Huawei Chen, Lara Ward, Anil Patel, Gilles Ouvry, Scott G. Lamont |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Chemistry Stereochemistry Stereoisomerism Combinatorial chemistry Bivalent (genetics) In vitro Bromodomain 03 medical and health sciences 030104 developmental biology 0302 clinical medicine In vivo 030220 oncology & carcinogenesis Drug Discovery Molecular Medicine Structure–activity relationship Potency Tumor growth inhibition |
| Zdroj: | Journal of Medicinal Chemistry. 59:7801-7817 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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