Pharmacokinetics-Driven Optimization of 7-Methylimidazo[1,5-a]pyrazin-8(7H)-one as Novel BRD4 Inhibitors

被引：7
|
作者：
Yang, Yifei [1 ,2 ]
Chen, Pan [1 ]
Zhao, Leilei [3 ]
Zhang, Fangqing [3 ]
Zhang, Huibin [3 ]
Zhou, Jinpei [1 ]
机构：
[1] China Pharmaceut Univ, Dept Med Chem, Nanjing 210009, Jiangsu, Peoples R China
[2] Univ Arkansas Med Sci, Coll Pharm, Dept Pharmaceut Sci, Little Rock, AR 72205 USA
[3] China Pharmaceut Univ, Jiangsu Key Lab Drug Discovery Metab Dis, Ctr Drug Discovery, Nanjing 210009, Jiangsu, Peoples R China
来源：
ACS MEDICINAL CHEMISTRY LETTERS | 2019年 / 10卷 / 12期
关键词：
BRD4; inhibitors; pharmacokinetics; pancreatic cancer; fluorescent probe; BET BROMODOMAINS; BIOLOGICAL EVALUATION; SELECTIVE-INHIBITION; EPIGENOME READER; CANCER; PROTEINS; INFLAMMATION; ACETYLATION; DERIVATIVES; DISCOVERY;
D O I：
10.1021/acsmedchemlett.9b00474
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
The BET bromodomain containing protein (BRD4) plays a key role in transcription regulation. Therefore, efforts to generate BRD4 inhibitors with excellent potency and DMPK properties are of clinical value. As a continuing work to improve the stability in in vitro metabolic experiments of liver microsomes of our previously reported 7-methylimidazo[1,5-a]pyrazin-8(7H)-one, our optimization of this poor pharmacokinetics focusing on the phenyl substituent is performed. Fortunately, compound 17 displayed subnanomolar potency (IC50 = 30 nM) against BRD4(1), and its liver microsome stability in human, rat, and mouse are more favorable than previously reported inhibitor 28. Compound 17 exhibited antitumor efficacy with no significant toxicity in xenograft models of pancreatic cancer. In addition, fluorescent probe and nuclei-specific dye were utilized to verify apoptosis-inducing of compound 17 via intranuclear potency in BXPC-3 cell line.
引用
收藏
页码：1680 / 1685
页数：11
相关论文
共 50 条
  • [11] FACILE SYNTHESIS OF IMIDAZO[1,5-a]PYRAZIN-8(7H)-ONES FROM MESOIONIC 1,3-OXAZOLIUM-5-OLATES VIA A MULTISTEP ONE-POT TRANSFORMATION
    Saijo, Ryosuke
    Uno, Hidemitsu
    Kawase, Masami
    HETEROCYCLES, 2016, 92 (11) : 2047 - 2058
  • [12] Synthesis of 8,9-dihydro[1,2,4]triazolo[1,5-a]-quinazolin-6(7H)-one derivatives
    A. A. Petrov
    A. N. Kasatochkin
    Russian Journal of Organic Chemistry, 2013, 49 : 502 - 507
  • [13] Synthesis of 8,9-dihydro[1,2,4]triazolo[1,5-a]-quinazolin-6(7H)-one derivatives
    Petrov, A. A.
    Kasatochkin, A. N.
    RUSSIAN JOURNAL OF ORGANIC CHEMISTRY, 2013, 49 (04) : 502 - 507
  • [14] Synthesis of 4H-Pyrazino[1,2-a]pyrimidine-4,9(8H)-diones and Imidazo[1,2-a]pyrazin-8(7H)-ones
    Raubo, Piotr
    Ladwa, Neal
    SYNLETT, 2012, (20) : 2935 - 2938
  • [15] SYNTHESIS AND CHEMILUMINESCENCE PROPERTIES OF 6-(4-METHOXYPHENYL)-2-METHYLIMIDAZO[1,2-A]-PYRAZIN-3(7H)-ONE AND 2-METHYL-6-(2-NAPHTHYL)-IMIDAZO[1,2-A]PYRAZIN-3(7H)-ONE
    TOYA, Y
    KAYANO, T
    SATO, K
    GOTO, T
    BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN, 1992, 65 (09) : 2475 - 2479
  • [16] Quantitative determination of the new substance 7-(4-fluorobenzyl)-3-thioxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyrazin-8(7H)-one as a potential pharmaceutical agent
    Netosova, Krystyna
    Zavada, Oksana
    Materiienko, Anna
    Zhuravel, Iryna
    Baiurka, Serhii
    CHEMIJA, 2021, 32 (01): : 28 - 33
  • [17] The Synthesis of Novel 7-(Substituted benzyl)-4,5-dihydro[1,2,3]triazolo[1,5-a]pyrazin-6(7H)-ones via Tandem Ugi-Huisgen Reactions
    Pokhodylo, Nazariy T.
    Tupychak, Mykola A.
    Goreshnik, Evgeny A.
    Obushak, Mykola D.
    SYNTHESIS-STUTTGART, 2022, 55 (06): : 977 - 988
  • [18] Surrogating and redirection of pyrazolo[1,5-a]pyrimidin-7(4H)-one core, a novel class of potent and selective DPP-4 inhibitors
    Deng, Xinxian
    Shen, Jian
    Zhu, Hui
    Xiao, Jia
    Sun, Ran
    Xie, Fangzhou
    Lam, Celine
    Wang, Juntao
    Qiao, Yixue
    Tavallaie, Mojdeh S.
    Hu, Yang
    Due, Yi
    Li, Jianqi
    Fu, Lei
    Jiang, Faqin
    BIOORGANIC & MEDICINAL CHEMISTRY, 2018, 26 (04) : 903 - 912
  • [19] 5-amino-8-(1-aminoethylidene)-8H-tetrazolo[1,5-a]pyridin-7one dihydrate
    Fusi, S
    Donati, D
    Ponticelli, F
    ACTA CRYSTALLOGRAPHICA SECTION E-STRUCTURE REPORTS ONLINE, 2003, 59 : O1589 - O1591
  • [20] X-RAY-ANALYSIS OF 6-ETHOXYCARBONYL-4-ETHYLPYRAZOLO[1,5-A]PYRIMIDIN-7(4H)-ONE AND 6-ETHOXYCARBONYL-4-ETHYL-1,2,4-TRIAZOLO[1,5-A]PYRIMIDIN-7(4H)-ONE
    CLAYTON, JP
    ROGERS, NH
    SMITH, VJ
    STEVENSON, R
    KING, TJ
    JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1, 1980, (07): : 1347 - 1351
12345