Discovery of RG7834: The First-in-Class Selective and Orally Available Small Molecule Hepatitis B Virus Expression Inhibitor with Novel Mechanism of Action

被引：52

作者：

Han, Xingchun ^{[1
]}

Zhou, Chengang ^{[1
]}

Jiang, Min ^{[1
]}

Wang, Yongguang ^{[1
]}

Wang, Jianhua ^{[1
]}

Cheng, Zhanling ^{[1
]}

Wang, Min ^{[1
]}

Liu, Yongqiang ^{[1
]}

Liang, Chungen ^{[1
]}

Wang, Jianping ^{[1
]}

Wang, Zhanguo ^{[1
]}

Weikert, Robert ^{[4
]}

Lv, Wenzhe ^{[2
]}

Xie, Jianxun ^{[2
]}

Yu, Xin ^{[3
]}

Zhou, Xue ^{[3
]}

Luangsay, Souphalone ^{[5
]}

Shen, Hong C. ^{[1
]}

Mayweg, Alexander V. ^{[1
]}

Javanbakht, Hassan ^{[5
]}

Yang, Song ^{[1
]}

机构：

[1] Roche Pharma Res & Early Dev, Roche Innovat Ctr, Dept Med Chem, Bld 5,720 Cailun Rd, Shanghai, Peoples R China

[2] Roche Pharma Res & Early Dev, Roche Innovat Ctr, Pharmaceut Sci, Bld 5,720 Cailun Rd, Shanghai, Peoples R China

[3] Roche Pharma Res & Early Dev, Roche Innovat Ctr, Discovery, Bld 5,720 Cailun Rd, Shanghai, Peoples R China

[4] Roche Pharma Res & Early Dev, Roche Innovat Ctr Basel, Dept Med Chem, Grenzacherstr 124, CH-4070 Basel, Switzerland

[5] Roche Pharma Res & Early Dev, Roche Innovat Ctr Basel, Discovery Virol, Grenzacherstr 124, CH-4070 Basel, Switzerland

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 61卷 / 23期

关键词：

BIOLOGICAL EVALUATION; DERIVATIVES; PYRIMIDINE; DESIGN; FNC;

D O I：

10.1021/acs.jmedchem.8b01245

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Chronic hepatitis B virus (HBV) infection is a serious public health burden, and current therapies cannot achieve satisfactory cure rate. There are high unmet medical needs of novel therapeutic agents with differentiated mechanism of action (MOA) from the current standard of care. RG7834, a compound from the dihydroquinolizinone (DHQ) chemical series, is a first-in-class highly selective and orally bioavailable HBV inhibitor which can reduce both viral antigens and viral DNA with a novel mechanism of action. Here we report the discovery of RG7834 from a phenotypic screening and the structure-activity relationship (SAR) of the DHQchemical series. RG7834 can selectively inhibit HBV but not other DNA or RNA viruses in a virus panel screening. Both in vitro and in vivo profiles of RG7834 are described herein, and the data support further development of this compound as a chronic HBV therapy.

引用

页码：10619 / 10634

页数：16

共 9 条

[1] Discovery of RG7834 and target identification: First-in-class selective and orally bioavailable small molecule HBV expression inhibitor with a novel mechanism of action
Yang, Song
[J]. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2019, 258
[2] A novel orally available small molecule that inhibits hepatitis B virus expression
Mueller, Henrik
Wildum, Steffen
Luangsay, Souphalone
Walther, Johanna
Lopez, Anais
Tropberger, Philipp
Ottaviani, Giorgio
Lu, Wenzhe
Parrott, Neil John
Zhang, Jitao David
Schmucki, Roland
Racek, Tomas
Hoflack, Jean-Christophe
Kueng, Erich
Point, Floriane
Zhou, Xue
Steiner, Guido
Luetgehetmann, Marc
Rapp, Gianna
Volz, Tassilo
Dandri, Maura
Yang, Song
Young, John A. T.
Javanbakht, Hassan
[J]. JOURNAL OF HEPATOLOGY, 2018, 68 (03) : 412 - 420
[3] Identification of prodigious and under-privileged structural features for RG7834 analogs as Hepatitis B virus expression inhibitor
Vijay H. Masand
Nahed N. E. El-Sayed
Vesna Rastija
Mithilesh M. Rathore
Maja Karnaš
[J]. Medicinal Chemistry Research, 2019, 28 : 2270 - 2278
[4] Identification of prodigious and under-privileged structural features for RG7834 analogs as Hepatitis B virus expression inhibitor
Masand, Vijay H.
El-Sayed, Nahed N. E.
Rastija, Vesna
Rathore, Mithilesh M.
Karnas, Maja
[J]. MEDICINAL CHEMISTRY RESEARCH, 2019, 28 (12) : 2270 - 2278
[5] A novel class of orally-available small molecules potently inhibiting hepatitis B and D virus entry
Unchwaniwala, Nuruddin
Contreras, Heidi
Li, Jinghu Carl
Azimova, Dinara
Tan, Joseph
Guo, Lida
de Sousa, Francielle Tramontini Gomes
Stray, Kirsten
Shen, Michael
Yu, Jiaxin
Windisch, Marc P.
Perron, Michel
Walker, Michael A.
Delaney, William E.
Zhong, Min
[J]. JOURNAL OF HEPATOLOGY, 2023, 78 : S1167 - S1167
[6] Discovery and validation of biomarkers to support clinical development of NXP800: A first-in-class orally active, small-molecule HSF1 pathway inhibitor
Workman, P.
Clarke, P. A.
Poele, R. Te
Powers, M.
Box, G.
De Billy, E.
Brandon, A. De Haven
Hallsworth, A.
Hayes, A.
McCann, H.
Sharp, S.
Valenti, M.
Raynaud, F. I.
Eccles, S. A.
Cheeseman, M.
Jones, K.
[J]. EUROPEAN JOURNAL OF CANCER, 2022, 174 : S35 - S35
[7] Antiviral agents 3. Discovery of a novel small molecule non-nucleoside inhibitor of Hepatitis B Virus (HBV)
Crosby, Ian T.
Bourke, David G.
Jones, Eric D.
Jeynes, Tyrone P.
Cox, Susan
Coates, Jonathan A. V.
Robertson, Alan D.
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2011, 21 (06) : 1644 - 1648
[8] Phase 1 trial of CA-170, a first-in-class, orally available, small molecule immune checkpoint inhibitor (ICI) dually targeting PD-L1 and VISTA, in patients with advanced solid tumors or lymphomas
Bang, Yung Jue
Powderly, John
Patel, Manish
Kim, Kyu Pyo
Lee, James
Brody, Joshua
Garcia-Corbacho, Javier
Rha, Sun Young
Meric-Bernstam, Funda
Hamilton, Erika
Ponce Aix, Santiago
Ramchandren, Radhakrishnan
Sosman, Jeffrey
Ahn, Myung Ju
Snozl, Mario
Falchook, Gerald
Martin, Marta Gil
Wang, Hongwei
Adams, Lisa
Caldwell, Christopher
Lazorchak, Adam
Wyant, Timothy
Ma, Anna
Tuck, David
Daud, Adil
[J]. JOURNAL FOR IMMUNOTHERAPY OF CANCER, 2017, 5
[9] OSI-906: A novel, potent, and selective first-in-class small molecule insulin-like growth factor 1 receptor (IGF-1R) inhibitor in phase I clinical trials
Volk, Brian
Buck, Elizabeth
Coate, Heather
Cooke, Andrew
Dong, Hanging
Eyzaguirre, Alexandra
Feng, Lixin
Foreman, Ken
Rosenfeld-Franklin, Maryland
Kleinberg, Andrew
Landfair, Darla
Mak, Gilda
Nigro, Anthony
O'Connor, Matthew
Pirritt, Caroline
Silva, Stacia
Siu, Kam
Steinig, Arno
Stolz, Kate
Tavares-Greco, Paula
Turton, Roy
Werner, Doug
Yao, Yan
Arnold, Lee
Gibson, Neil W.
Pachter, Jon A.
Wild, Robert
Ji, Qun-Sheng
Mulvihill, Mark J.
[J]. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2009, 238

← 1 →