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Janus-Associated Kinase 1 (JAK1) Inhibitors as Potential Treatment for Immune Disorders Ahmed F. Abdel-Magid* Therachem Research Medilab (India) Pvt. Ltd., Jaipur, India Patent Application Title:
Compounds and Methods for Inhibiting JAK
Patent Application Number:
WO 2017/050938 Al
Publication date:
30 March 2017
Priority Application:
US 62/232,629
Priority date:
25 September 2015
Inventors:
Astrand, A. B. M.; Grimster, N. P.; Kawatkar, S.; Kettle, J. G.; Nilsson, M. K.; Ruston, L. L.; Su, Q.; Vasbinder, M. M.; WinterHolt, J. J.; Wu, D.; Yang, W.; Grecu, T.; Mccabe, J.; Woessner, R. D.; Chuaqui, C. E.
Applicants:
AstraZeneca AB [SE/SE]; SE-151 85 Södertalje (SE)
Disease Area:
Immune disorders, such as bone marrow disorders, rheumatoid arthritis, psoriasis, Crohn’s disease, lupus, and multiple sclerosis
Summary:
The invention in this patent application relates to 3-(2-aminopyrimidin-4-yl)indole derivatives represented generally by formula (I). These compounds are JAK1 inhibitors and may be useful for the treatment of a number of immune disorders, such as bone marrow disorders, rheumatoid arthritis, psoriasis, Crohn’s disease, lupus, and multiple sclerosis.
Biological Target:
Janus-associated kinase 1 (JAK1)
The Janus-associated kinase family (JAKs) contains four known members named JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). They are cytoplasmic nonreceptor tyrosine kinases that are found in hematopoietic cells and reside on the cytoplasmic side of Type I and II cytokine receptors. JAKs play critical roles in cytokine and growth factor mediated signal transduction and in the immune defense. Certain cytokine and/or growth factor receptors (such as erythropoietin, thrombopoietin, interleukins, and interferon receptors) lack the catalytic ability to initiate downstream signaling. By binding to one (or more) of the JAK family members, these receptors can be activated to perform this function. This binding induces conformational changes that allow JAKs to be activated and phosphorylate the tyrosine residues on the receptor cytoplasmic domains and even on themselves (autophosphorylation). This creates active sites that attract and bind with signaling proteins such as the signal transducer and activator of transcription (STAT). The binding of a STAT protein to an activated JAK results in phosphorylation, subsequent dimerization, and translocation of STAT to the nucleus, where it modulates target gene transcription. The STAT family contains seven transcription factor members named STAT1, 2, 3, 4, 5a, 5b, and 6. The phosphorylation and subsequent activation of STAT3 has been linked to a wide range of cancers and hyperproliferative disorders and was also associated with poor prognosis in several cancers. Persistently activated STAT3 is oncogenic and has been shown to drive the expression of cellular proteins that contribute to the fundamental cancer progression processes including survival, proliferation, invasion, and angiogenesis. A typical mechanism of STAT3 activation in cancer cells is believed to occur via autocrine or paracrine stimulation of JAK/STAT3 signaling by members of the interleukin-6 (IL-6) cytokine family. JAK1 is the key JAK kinase that mediates this STAT3 activation process. Inactivation of negative regulatory proteins, such as the suppressors of cytokine signaling (SOCS) or protein inhibitor of activated STATs (PIAS) proteins, have also been shown to influence the activation of the JAK/STAT signaling pathway in cancer. JAK1/STAT3 signaling pathway activation in several human tumors may also occur as a feedback resistance mechanism in response to inhibition of driver oncogenic pathways in cancer cells, such as the mutated epidermal growth factor receptor (EGFR) in nonsmall cell lung cancer (NSCLC) or the mitogen-activated protein kinase (MAPK) pathway in KRAS mutant tumors. Thus, the inhibition of JAK1 may provide a means of potentiating the therapeutic benefit of a variety of targeted cancer therapies. Cancer cachexia is a debilitating condition that affects advanced cancer patients and causes significant skeletal muscle wasting. It contributes significantly to increased patient mortality and poor response to chemotherapy. One of the factors that plays a fundamental role in this condition is elevated levels of inflammatory cytokines, such as IL-6, which signal through the JAK/STAT pathway. Thus, there is a potential benefit for JAK1 inhibition in ameliorating cancer cachexia. JAK1 plays a critical role in signal transduction mediated by class II cytokine receptors, the cytokine receptor common subunit γ (γc), the glycoprotein 130 (gp130) subunit, and granulocyte-colony stimulating factor G-CSF. It also drives the activities of the immune-relevant γc cytokines. Therefore, JAK1 inhibitors such as the compounds of formula I described in this patent application, which exhibit up to 100 times selectivity for the inhibition of JAK1 over JAK2, may provide useful treatments for a number of immune disorders, such as bone marrow disorders, rheumatoid arthritis, psoriasis, Crohn’s disease, lupus, and multiple sclerosis.
Received: May 18, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.7b00209 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
Patent Highlight
Important Compound Classes:
Key Structures:
The inventors described the synthesis procedures and structures of 69 compounds of formula (I) including the following representative examples:
Biological Assay:
• Enzyme Inhibition Studies • Cellular pSTAT3 Assay
Biological Data:
• The results from the enzyme inhibition studies assay indicate that the compounds of the invention exhibit up to 100 times selectivity for the inhibition of JAK1 over JAK2.
• The results from cellular pSTAT3 assay demonstrate good correlation between cellular inhibition of STAT3 phosphorylation in NCI-H1975 cells and JAK1 inhibition. Data for the above representative examples are listed in the following table:
Recent Review Articles:
1. Nakayamada, S.; Kubo, S.; Iwata, S.; Tanaka, Y. BioDrugs 2016, 30( 5), 407−419. 2. Menet, C. J.; Mammoliti, O.; Lopez-Ramos, M. Future Med. Chem. 2015, 7 (2), 203−235. 3. Norman, P. Expert Opinion on Therapeutic Patents 2014, 24 (2), 231−237.
B
DOI: 10.1021/acsmedchemlett.7b00209 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
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Patent Highlight
AUTHOR INFORMATION
Corresponding Author
*Address: 1383 Jasper Drive, Ambler, Pennsylvania 19002, United States. Tel: 215-913-7202. E-mail:
[email protected]. Notes
The author declares no competing financial interest.
C
DOI: 10.1021/acsmedchemlett.7b00209 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
