Design, synthesis and evaluation of pyrrolo[2,3-d]pyrimidine-phenylamide hybrids as potent Janus kinase 2 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2016.04.027

Janus kinase 2 (JAK2) plays an essential role in the signaling of hormone-like cytokines and growth factors, which has been convinced as an important target of myeloproliferative neoplasms (MPNs) therapy. In this study, a series of novel pyrrolo[2,3-d]pyr

Full text of DOI:10.1016/j.bmcl.2016.04.027

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Accepted Manuscript
Design, synthesis and evaluation of pyrrolo[2,3-d]pyrimidine-phenylamide hy-
brids as potent Janus Kinase 2 inhibitors
Tingfang Wang, Xiaofei Liu, Meixi Hao, Jianan Qiao, Caoyun Ju, Lingjing Xue,
Can Zhang
PII:
S0960-894X(16)30400-0
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.04.027
BMCL 23789
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
9 March 2016
7 April 2016
12 April 2016
Please cite this article as: Wang, T., Liu, X., Hao, M., Qiao, J., Ju, C., Xue, L., Zhang, C., Design, synthesis and
evaluation of pyrrolo[2,3-d]pyrimidine-phenylamide hybrids as potent Janus Kinase 2 inhibitors, Bioorganic &
Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.04.027
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Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Design,
synthesis
and
evaluation
of
pyrrolo[2,3-d]pyrimidine-phenylamide hybrids as potent Janus
Kinase 2 inhibitors
Tingfang Wang, Xiaofei Liu, Meixi Hao, Jianan Qiao, Caoyun Ju,
Lingjing Xue*, Can Zhang*
State Key Laboratory of Natural Medicines and Jiangsu Key
Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug
Discovery, China Pharmaceutical University, 24 Tong Jia Xiang,
Nanjing 210009, China
*Corresponding author.
E-mail
addresses:
xuelingjing65@163.com
(L.
Xue),
zhangcan@cpu.edu.cn (C. Zhang).
1

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
ABSTRACT
Janus kinase 2 (JAK2) plays an essential role in the signaling of hormone-like cytokines and
growth factors, which has been convinced as an important target of myeloproliferative
neoplasms (MPNs) therapy. In this study, series of novel
a
pyrrolo[2,3-d]pyrimidine-phenylamide hybrids were designed and synthesized as potential
JAK2 inhibitors through hybridization strategy. In vitro biological studies showed that most
of these compounds exhibited potent activity against JAK2. Especially, compound 16c was
identified as a suitable lead compound, which showed favorable pharmacokinetic profiles in
rats (F = 73.57%), excellent in vitro efficacy against erythroleukemic cells (TF-1, IC50 = 0.14
μM), and high selectivity for JAK2 (IC50 = 6 nM with >97-fold selectivity vs JAK3).
Keywords：Pyrrolo[2,3-d]pyrimidine, Hybridization, JAK2 inhibitors, Myeloproliferative
neoplasms
2

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The Janus kinases (including JAK1, JAK2, JAK3, and TYK2) are a pivotal family of
intracellular non-receptor protein tyrosine kinases that play prominent roles in cytokine
and growth factor-mediated receptor signaling.1 Once cytokines binding to the receptors, the
receptor-associated JAKs can be activated and subsequently phosphorylate signal
transducers and activators of transcription proteins (STATs). The phosphorylated STATs
dimerize and migrate to the nucleus where their respective target genes expression are
modulated, consequently leading to the influence of cell proliferation, differentiation and
survival.2 Among the JAKs, JAK2 is essential for signaling through hormone-like cytokines
and growth factors such as interleukin-3 (IL-3), IL-5, granulocyte–macrophage-colony
stimulating factor (GM-CSF)，erythropoietin (EPO), and thrombopoietin (TPO).3 Herein, the
JAK2 has been implicated in the pathogenesis of myeloid malignancies.4 Furthermore, an
activating mutation of JAK2 (V617F) was reported in a majority of patients with
myeloproliferative neoplasms (MPNs) (＞95% in PV (polycythemia vera), ＞50% in
essential ET (thrombocythemia) and ＞50% in primary MF (myelofibrosis)).5 Since this
mutation located in the JH2 pseudokinase (Janus Homology 2) domain of JAK2, which is
required for the inhibition of basal kinase activity, thus leading to increased tyrosine kinase
activity and cytokine hypersensitivity.6 As a consequence, JAK2 is closely associated with the
MPNs, which means that inhibition of JAK2 can lead to the inhibition of the aberrant
JAK2/STATs signaling, therefore represents an attractive therapeutic approach for MPNs.
So far, many JAK2 inhibitors have been reported and tested in preclinical and clinical
trials. Notably, Ruxolitinib (Figure 1) was approved by FDA in 2011 for the treatment of
patients with intermediate and high-risk MF.7 In addition, Fedratinib (SAR302503),8
Lestaurtinib (CEP-701),9 Momelotinib (CYT-387),10 Pacritinib (SB1518),11 Gandotinib
(LY2784544),12 BMS-911543,13 XL01914 and CEP-3377915 are also being investigated in
clinical trials. However, Ruxolitinib, a JAK1/JAK2 dual inhibitor, has been observed to gain
the immunosuppressive side effects due to inhibition of JAK1 or JAK3, which suggest to
pursue the identification of a JAK2 selective inhibitor in order to increase safety.16 The
discovery of selective JAK2 inhibitors has been disclosed in numerous publications,17
however, they are far from being a solution to all clinical issues in patients with MPNs.18
3