Design and synthesis of a biaryl series as inhibitors for the bromodomains of CBP/P300

[Display omitted] A novel, potent, and orally bioavailable inhibitor of the bromodomain of CBP, compound 35 (GNE-207), has been identified through SAR investigations focused on optimizing al bicyclic heteroarene to replace the aniline present in the published GNE-272 series. Compound 35 has excellen...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2018-01, Vol.28 (1), p.15-23
Hauptverfasser:	Lai, Kwong Wah, Romero, F. Anthony, Tsui, Vickie, Beresini, Maureen H., de Leon Boenig, Gladys, Bronner, Sarah M., Chen, Kevin, Chen, Zhongguo, Choo, Edna F., Crawford, Terry D., Cyr, Patrick, Kaufman, Susan, Li, Yingjie, Liao, Jiangpeng, Liu, Wenfeng, Ly, Justin, Murray, Jeremy, Shen, Weichao, Wai, John, Wang, Fei, Zhu, Caicai, Zhu, Xiaoyu, Magnuson, Steven
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Binding Sites Biphenyl Compounds - chemical synthesis Biphenyl Compounds - chemistry Biphenyl Compounds - metabolism Bromodomain CBP inhibitor Crystallography, X-Ray Drug Design Half-Life Humans Hydrogen Bonding Inhibitory Concentration 50 Mice Microsomes, Liver - metabolism Molecular Dynamics Simulation Nuclear Proteins - antagonists & inhibitors Nuclear Proteins - metabolism p300-CBP Transcription Factors - antagonists & inhibitors p300-CBP Transcription Factors - metabolism Protein Structure, Tertiary Rats Structure-Activity Relationship Transcription Factors - antagonists & inhibitors Transcription Factors - metabolism Volume of distribution
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Zusammenfassung:	[Display omitted] A novel, potent, and orally bioavailable inhibitor of the bromodomain of CBP, compound 35 (GNE-207), has been identified through SAR investigations focused on optimizing al bicyclic heteroarene to replace the aniline present in the published GNE-272 series. Compound 35 has excellent CBP potency (CBP IC50 = 1 nM, MYC EC50 = 18 nM), a selectively index of >2500-fold against BRD4(1), and exhibits a good pharmacokinetic profile.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2017.11.025