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. 2015 Mar 25;7(2):145-50.
doi: 10.1021/ml500411h. eCollection 2016 Feb 11.

Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains

Alexander M Taylor  1 , Rishi G Vaswani  1 , Victor S Gehling  1 , Michael C Hewitt  1 , Yves Leblanc  1 , James E Audia  1 , Steve Bellon  1 , Richard T Cummings  1 , Alexandre Côté  1 , Jean-Christophe Harmange  1 , Hari Jayaram  1 , Shivangi Joshi  1 , Jose M Lora  1 , Jennifer A Mertz  1 , Adrianne Neiss  1 , Eneida Pardo  1 , Christopher G Nasveschuk  1 , Florence Poy  1 , Peter Sandy  1 , Jeremy W Setser  1 , Robert J Sims 3rd  1 , Yong Tang  1 , Brian K Albrecht  1
Affiliations

Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains

Alexander M Taylor et al. ACS Med Chem Lett. .

Abstract

Inhibition of the bromodomains of the BET family, of which BRD4 is a member, has been shown to decrease myc and interleukin (IL) 6 in vivo, markers that are of therapeutic relevance to cancer and inflammatory disease, respectively. Herein we report substituted benzo[b]isoxazolo[4,5-d]azepines and benzotriazolo[4,3-d][1,4]diazepines as fragment-derived novel inhibitors of the bromodomain of BRD4. Compounds from these series were potent and selective in cells, and subsequent optimization of microsomal stability yielded representatives that demonstrated dose- and time-dependent reduction of plasma IL-6 in mice.

Keywords: BET; BRD4; Bromodomain; IL-6 inhibition.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Overview of the Origin and Development of Different Azepine-Derived BET Inhibitors
Figure 1
Figure 1
(A) A 1.4 Å cocrystal structure of 3 (green) bound to BRD4 BD-1. PDB code: 4Z1Q. Key H-bonding interactions are indicated. (B) An overlay of a co-crystal structure of 13 (green) with one of CPI-3 (gray) shows the similarity in binding modes between the two series (RMSD = 0.43 for common heavy atoms). PDB code: 4X2I.
Figure 2
Figure 2
Suppression of IL-6 release in mouse correlates with plasma exposure of 3 following 15 mg/kg dosing PO. Free concentration of 3 calculated based on 98% PPBmouse. Dashed line indicates cellular IL-6 EC50.
See this image and copyright information in PMC

References

    1. Wu S. Y.; Chiang C. M. The double bromodomain-containing chromatin adaptor Brd4 and transcriptional regulation. J. Biol. Chem. 2007, 282, 13141–45. - PubMed
    1. Dey A.; Chitsaz F.; Abbasi A.; Misteli T.; Ozato K. The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitosis. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 8758–63. - PMC - PubMed
    1. Miyoshi M.; Ooike S.; Iwata K.; Hikawa H.; Sugahara K. Antitumor Compounds. WO 2009/084693A1, published Sept. 9, 2009.
    1. Filippakopoulos P.; Qi J.; Picaud S.; Shen Y.; Smith W. B.; Fedorov O.; Morse E. M.; Keates T.; Hickman T. T.; Felletar I.; Philpott M.; Munro S.; McKeown M. R.; Wang Y.; Christie A. L.; West N.; Cameron M. J.; Schwartz B.; Heightman T. D.; La Thangue N.; French C. A.; Wiest O.; Kung A. L.; Knapp S.; Bradner J. E. Selective inhibition of BET bromodomains. Nature 2010, 468, 1067–73. - PMC - PubMed
    1. Nicodeme E.; Jeffrey K. L.; Schaefer U.; Beinke S.; Dewell S.; Chung C. W.; Chandwani R.; Marazzi I.; Wilson P.; Coste H.; White J.; Kirilovsky J.; Rice C. M.; Lora J. M.; Prinjha R. K.; Lee K.; Tarakhovsky A. Suppression of inflammation by a synthetic histone mimic. Nature 2010, 468, 1119–23. - PMC - PubMed