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)
Robert H. Bradbury, Rowena Callis, Gregory R. Carr, Huawei Chen, Edwin Clark, Lyman Feron, Steve Glossop, Mark A. Graham, Maureen Hattersley, Chris Jones, Scott G. Lamont, Gilles Ouvry, Anil Patel, Joe Patel, Alfred A. Rabow, Craig A. Roberts, Stephen Stokes, Natalie Stratton, Graeme E. Walker, Lara Ward, David Whalley, David Whittaker, Gail Wrigley, Michael J. Waring
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 programme, the compounds were optimised for BRD4 potency and physical properties. The optimised compound from this campaign exhibited excellent pharmacokinetic profile and exhibited high potency in vitro and in vivo effecting c-Myc downregulation and tumour 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.
Pharmacology, Toxicology and Pharmaceutical Science
5
7%
Agricultural and Biological Sciences
4
6%
Medicine and Dentistry
4
6%
Other
4
6%
Unknown
15
22%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 11. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 30 December 2022.
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#2,924,059
of 23,452,723 outputs
Outputs from Journal of Medicinal Chemistry
#2,825
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Outputs of similar age
#51,540
of 343,488 outputs
Outputs of similar age from Journal of Medicinal Chemistry
#23
of 162 outputs
Altmetric has tracked 23,452,723 research outputs across all sources so far. Compared to these this one has done well and is in the 87th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 22,315 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 6.7. This one has done well, scoring higher than 87% of its peers.
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We're also able to compare this research output to 162 others from the same source and published within six weeks on either side of this one. This one has done well, scoring higher than 84% of its contemporaries.
