- Discovery of Potent and Orally Effective Dual Janus Kinase 2/FLT3 Inhibitors for the Treatment of Acute Myelogenous Leukemia and Myeloproliferative Neoplasms
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Herein, we describe the design, synthesis, and structure-activity relationships of a series of unique 4-(1H-pyrazol-4-yl)-pyrimidin-2-amine derivatives that selectively inhibit Janus kinase 2 (JAK2) and FLT3 kinases. These screening cascades revealed that 18e was a preferred compound, with IC50 values of 0.7 and 4 nM for JAK2 and FLT3, respectively. Moreover, 18e was a potent JAK2 inhibitor with 37-fold and 56-fold selectivity over JAK1 and JAK3, respectively, and possessed an excellent selectivity profile over the other 100 representative kinases. In a series of cytokine-stimulated cell-based assays, 18e exhibited a higher JAK2 selectivity over other JAK isoforms. The oral administration of 60 mg/kg of 18e could significantly inhibit tumor growth, with a tumor growth inhibition rate of 93 and 85% in MV4-11 and SET-2 xenograft models, respectively. Additionally, 18e showed an excellent bioavailability (F = 58%), a suitable half-life time (T1/2 = 4.1 h), a satisfactory metabolic stability, and a weak CYP3A4 inhibitory activity, suggesting that 18e might be a potential drug candidate for JAK2-driven myeloproliferative neoplasms and FLT3-internal tandem duplication-driven acute myelogenous leukemia.
- Yang, Tao,Hu, Mengshi,Qi, Wenyan,Yang, Zhuang,Tang, Minghai,He, Jun,Chen, Yong,Bai, Peng,Yuan, Xue,Zhang, Chufeng,Liu, Kongjun,Lu, Yulin,Xiang, Mingli,Chen, Lijuan
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p. 10305 - 10320
(2019/11/19)
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- CARBOXYLIC ACID AROMATIC AMIDES AS ANTAGONISTS OF BRADYKININ B1 RECEPTOR
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The present invention relates to carboxylic acid aromatic amides compounds of general formula (I) as described and defined herein, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing
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Page/Page column 147; 148
(2018/07/29)
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- TRIAZOLOPYRIDINE INHIBITORS OF MYELOPEROXIDASE
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The present invention provides compounds of Formula (I). wherein A and Z are as defined in the specification, and compositions comprising any of such novel compounds. These compounds are myeloperoxidase (MPO) inhibitors and may be useful for for the treatment and/or prophylaxis of atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases.
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Page/Page column 96; 99
(2017/10/18)
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- INHIBITORS OF ACTIVIN RECEPTOR-LIKE KINASE
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Described herein are compounds that inhibit ALK2 and its mutants, pharmaceutical compositions including such compounds, and methods of using such compounds and compositions.
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Page/Page column 272
(2017/11/10)
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- PROTEIN KINASE INHIBITORS
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A compound of formula (I), wherein R3, R4, G, B, M, and Z are as defined in the claims, and pharmaceutically acceptable salts thereof are disclosed. The compounds of formula (I) possess utility as FGFR inhibitors and are useful in the treatment of a condition, where FGFR kinase inhibition is desired, such as cancer.
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Paragraph 0188
(2015/02/18)
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- SUBSTITUTED PYRIDOPYRAZINES AS NOVEL SYK INHIBITORS
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Provided are pyridopyrazine compounds of formula (1), pharmaceutical compositions thereof and methods of use therefore, wherein R1, R2, R3, R4 and m are as defined in the specification.
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Paragraph 0334; 0335; 0336
(2014/05/08)
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- PYRIDO[3,4-B]PYRAZINE DERIVATIVES AS SYK INHIBITORS
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A compound of formula (I): or a salt thereof; which is an inhibitor of spleen tyrosine kinase (Syk) and therefore potentially of use in treating diseases resulting from inappropriate activation of mast cells, macrophages, and B-cells and related inflammatory responses and tissue damage, for instance inflammatory disease and/or allergic disorders, and in cancer therapy, specifically heme malignancies, and autoimmune conditions.
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Paragraph 0571; 0572; 0573
(2014/02/15)
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- PROTEIN KINASE INHIBITORS
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A compound of formula (I), wherein R3, R4, G, B, M, and Z are as defined in the claims, and pharmaceutically acceptable salts thereof are disclosed. The compounds of formula (I) possess utility as FGFR inhibitors and are useful in the treatment of a condition, where FGFR kinase inhibition is desired, such as cancer.
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Page/Page column 48
(2013/04/25)
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- PYRIDO[3,4-B]PYRAZINE DERIVATIVES AS SYK INHIBITORS
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A compound of formula (I) or a salt thereof; which is an inhibitor of spleen tyrosine kinase (Syk) and therefore potentially of use in treating diseases resulting from inappropriate activation of mast cells, macrophages, and B-cells and related inflammatory responses and tissue damage, for instance inflammatory disease and/or allergic disorders, and in cancer therapy, specifically heme malignancies, and autoimmune conditions.
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Page/Page column 65
(2012/10/07)
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- 4, 6-DISUBSTITUTED 2-AMINO-PYRIMIDINES AS HISTAMINE H4 RECEPTOR MODULATORS
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The present invention relates to substituted heterocyclic compounds of Formula (I) or pharmaceutically acceptable salts or N-oxides or quaternary ammonium salts thereof wherein constituent members are provided hereinwith, as well as their compositions and methods of use, which are histamine H4 receptor inhibitors/antagonists useful in the treatment of histamine H4 receptor-associated conditions or diseases or disorders including, for example, inflammatory diseases or disorders, pruritus, and pain.
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Page/Page column 172
(2010/07/09)
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