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Optimisation 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)

Lookup NU author(s): Professor Mike Waring



This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).


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.

Publication metadata

Author(s): Bradbury RH, Callis R, Carr GR, Chen H, Clark E, Feron L, Glossop S, Graham MA, Hattersley M, Jones C, Lamont SG, Ouvry G, Patel A, Patel J, Rabow AA, Roberts CA, Stokes S, Stratton N, Walker GE, Ward L, Whalley D, Whittaker D, Wrigley G, Waring MJ

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 2016

Volume: 59

Issue: 17

Pages: 7801-7817

Online publication date: 15/08/2016

Acceptance date: 15/08/2016

Date deposited: 15/08/2016

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

Publisher: American Chemical Society


DOI: 10.1021/acs.jmedchem.6b00070


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