Strategies to Mitigate the Bioactivation of 2-Anilino-7-Aryl-Pyrrolo[2,1-f][1,2,4]triazines: Identification of Orally Bioavailable, Efficacious ALK Inhibitors

被引：25

作者：

Mesaros, Eugen F. ^{[1
]}

Thieu, Tho V. ^{[1
]}

Wells, Gregory J. ^{[1
]}

Zificsak, Craig A. ^{[1
]}

Wagner, Jason C. ^{[1
]}

Breslin, Henry J. ^{[1
]}

Tripathy, Rabindranath ^{[1
]}

Diebold, James L. ^{[1
]}

McHugh, Robert J. ^{[1
]}

Wohler, Ashley T. ^{[1
]}

Quail, Matthew R. ^{[1
]}

Wan, Weihua ^{[1
]}

Lu, Lihui ^{[1
]}

Huang, Zeqi ^{[1
]}

Albom, Mark S. ^{[1
]}

Angeles, Thelma S. ^{[1
]}

Wells-Knecht, Kevin J. ^{[1
]}

Aimone, Lisa D. ^{[1
]}

Cheng, Mangeng ^{[1
]}

Ator, Mark A. ^{[1
]}

Ott, Gregory R. ^{[1
]}

Dorsey, Bruce D. ^{[1
]}

机构：

[1] Cephalon Inc, Worldwide Discovery Res, W Chester, PA 19380 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 01期

关键词：

ANAPLASTIC LYMPHOMA KINASE; SMALL-MOLECULE INHIBITOR; EML4-ALK FUSION GENE; LARGE-CELL LYMPHOMA; THERAPEUTIC TARGET; PATHOGENESIS; GROWTH; CANCER;

D O I：

10.1021/jm2010767

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Chemical strategies to mitigate cytochrome P450-mediated bioactivation of novel 2,7-disubstituted pyrrolo[2,1-f][1,2,4]triazine ALK inhibitors are described along with synthesis and biological activity. Piperidine-derived analogues showing minimal microsomal reactive metabolite formation were discovered. Potent, selective, and metabolically stable ALK inhibitors from this class were identified, and an orally bioavailable compound (32) with antitumor efficacy in ALK-driven xenografts in mouse models was extensively characterized.

引用

页码：115 / 125

页数：11

共 14 条

[1] 2,7-Disubstituted-pyrrolo[2,1-f][1,2,4]triazines: New Variant of an Old Template and Application to the Discovery of Anaplastic Lymphoma Kinase (ALK) Inhibitors with in Vivo Antitumor Activity
Ott, Gregory R.
Wells, Gregory J.
Thieu, Tho V.
Quail, Matthew R.
Lisko, Joseph G.
Mesaros, Eugen F.
Gingrich, Diane E.
Ghose, Arup K.
Wan, Weihua
Lu, Lihui
Cheng, Mangeng
Albom, Mark S.
Angeles, Thelma S.
Huang, Zeqi
Aimone, Lisa D.
Ator, Mark A.
Ruggeri, Bruce A.
Dorsey, Bruce D.
JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (18) : 6328 - 6341
[2] Novel pyrrolo[2,1-f][1,2,4]triazin-4-amines: Dual inhibitors of EGFR and HER2 protein tyrosine kinases
Fink, Brian E.
Norris, Derek
Mastalerz, Harold
Chen, Ping
Goyal, Bindu
Zhao, Yufen
Kim, Soong-Hoon
Vite, Gregory D.
Lee, Francis Y.
Zhang, Hongjian
Oppenheimer, Simone
Tokarski, John S.
Wong, Tai W.
Gavai, Ashvinikumar V.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2011, 21 (02) : 781 - 785
[3] Pyrrolo[2,1-f][1,2,4]triazine: a promising fused heterocycle to target kinases in cancer therapy
Sarbjit Singh
Divya Utreja
Vimal Kumar
Medicinal Chemistry Research, 2022, 31 : 1 - 25
[4] Pyrrolo[2,1-f][1,2,4]triazine: a promising fused heterocycle to target kinases in cancer therapy
Singh, Sarbjit
Utreja, Divya
Kumar, Vimal
MEDICINAL CHEMISTRY RESEARCH, 2022, 31 (01) : 1 - 25
[5] Design, synthesis and antiproliferative activity evaluation of a series of pyrrolo [2,1-f] [1,2,4] triazine derivatives
Xiang, Hao-Yue
Chen, Yan-Hong
Wang, Yi
Zhang, Xi
Ding, Jian
Meng, Ling-Hua
Yang, Chun-Hao
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2020, 30 (12)
[6] Piperidine-3,4-diol and piperidine-3-ol derivatives of pyrrolo [2,1-f][1,2,4]triazine as inhibitors of anaplastic lymphoma kinase
Mesaros, Eugen F.
Angeles, Thelma S.
Albom, Mark S.
Wagner, Jason C.
Aimone, Lisa D.
Wan, Weihua
Lu, Lihui
Huang, Zeqi
Olsen, Mark
Kordwitz, Emily
Haltiwanger, R. Curtis
Landis, Amy J.
Cheng, Mangeng
Ruggeri, Bruce A.
Ator, Mark A.
Dorsey, Bruce D.
Ott, Gregory R.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2015, 25 (05) : 1047 - 1052
[7] Discovery of an Orally Efficacious Imidazo[5,1-f][1,2,4]triazine Dual Inhibitor of IGF-1R and IR
Jin, Meizhong
Gokhale, Prafulla C.
Cooke, Andy
Foreman, Kenneth
Buck, Elizabeth
May, Earl W.
Feng, Lixin
Bittner, Mark A.
Kadalbajoo, Mridula
Landfair, Darla
Siu, Kam W.
Stolz, Kathryn M.
Werner, Douglas S.
Laufer, Radoslaw S.
Li, An-Hu
Dong, Hanqing
Steinig, Arno G.
Kleinberg, Andrew
Yao, Yan
Pachter, Jonathan A.
Wild, Robert
Mulvihill, Mark J.
ACS MEDICINAL CHEMISTRY LETTERS, 2010, 1 (09): : 510 - 515
[8] Design and Development of Novel Hybrids Based on Pyrrolo[2,1-f][1,2,4]Triazine and 1-(Methylpiperidin-4-yl) Aniline-Based Analogs: Exploring the Utility as Anticancer Agents via MERTK Inhibition
Sathe, Balaji Dashrath
Jaiswal, Shivani
Kumar, Devendra
Singh, Thakur Gurjeet
Nainwal, Nidhi
Rawat, Pramod
Yadav, Savita
Kumar, Bhupinder
Dwivedi, Ashish Ranjan
Rathod, S. V.
CHEMICAL BIOLOGY & DRUG DESIGN, 2024, 104 (06)
[9] Synthesis of carbon-11-labeled 4-(phenylamino)-pyrrolo[2,1-f][1,2,4] triazine derivatives as new potential PET tracers for imaging of p38α mitogen-activated protein kinase
Wang, Min
Gao, Mingzhang
Zheng, Qi-Huang
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2014, 24 (16) : 3700 - 3705
[10] Identification and optimisation of a series of N-(4-anilino-2-pyridyl)acetamide activin receptor-like kinase 1 (ALK1) inhibitors
Goldberg, Frederick W.
Daunt, Paula
Pearson, Stuart E.
Greenwood, Ryan
Grist, Matthew
Debreczeni, Judit E.
MEDCHEMCOMM, 2016, 7 (06) : 1204 - 1208

← 1 2 →