WO2014118556A3 - Selective inhibitors and allosteric activators of sphingosine kinase - Google Patents
Selective inhibitors and allosteric activators of sphingosine kinase Download PDFInfo
- Publication number
- WO2014118556A3 WO2014118556A3 PCT/GB2014/050264 GB2014050264W WO2014118556A3 WO 2014118556 A3 WO2014118556 A3 WO 2014118556A3 GB 2014050264 W GB2014050264 W GB 2014050264W WO 2014118556 A3 WO2014118556 A3 WO 2014118556A3
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- WO
- WIPO (PCT)
- Prior art keywords
- sphingosine kinase
- selective inhibitors
- sphingosine
- allosteric activators
- inhibitors
- Prior art date
Links
- 108010035597 sphingosine kinase Proteins 0.000 title abstract 2
- ZDRVLAOYDGQLFI-UHFFFAOYSA-N 4-[[4-(4-chlorophenyl)-1,3-thiazol-2-yl]amino]phenol;hydrochloride Chemical compound Cl.C1=CC(O)=CC=C1NC1=NC(C=2C=CC(Cl)=CC=2)=CS1 ZDRVLAOYDGQLFI-UHFFFAOYSA-N 0.000 title 1
- 229940124639 Selective inhibitor Drugs 0.000 title 1
- 239000012190 activator Substances 0.000 title 1
- 230000003281 allosteric effect Effects 0.000 title 1
- DUYSYHSSBDVJSM-KRWOKUGFSA-N sphingosine 1-phosphate Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)COP(O)(O)=O DUYSYHSSBDVJSM-KRWOKUGFSA-N 0.000 abstract 4
- 102100039024 Sphingosine kinase 1 Human genes 0.000 abstract 3
- 102100027662 Sphingosine kinase 2 Human genes 0.000 abstract 3
- 201000010099 disease Diseases 0.000 abstract 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 2
- 239000003112 inhibitor Substances 0.000 abstract 2
- WWUZIQQURGPMPG-UHFFFAOYSA-N (-)-D-erythro-Sphingosine Natural products CCCCCCCCCCCCCC=CC(O)C(N)CO WWUZIQQURGPMPG-UHFFFAOYSA-N 0.000 abstract 1
- 206010016654 Fibrosis Diseases 0.000 abstract 1
- 206010028980 Neoplasm Diseases 0.000 abstract 1
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 abstract 1
- 101710156532 Sphingosine kinase 2 Proteins 0.000 abstract 1
- 208000032594 Vascular Remodeling Diseases 0.000 abstract 1
- 230000003510 anti-fibrotic effect Effects 0.000 abstract 1
- 230000001028 anti-proliverative effect Effects 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 201000011510 cancer Diseases 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 abstract 1
- 230000004761 fibrosis Effects 0.000 abstract 1
- 230000003463 hyperproliferative effect Effects 0.000 abstract 1
- 230000003834 intracellular effect Effects 0.000 abstract 1
- 150000003410 sphingosines Chemical class 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
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- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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- C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
- C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
- C07C215/08—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with only one hydroxy group and one amino group bound to the carbon skeleton
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Abstract
Sphingosine 1-phosphate (S1P) is involved in hyper-proliferative diseases, such as cancer and vascular remodeling in pulmonary arterial hypertension. Inhibitors of sphingosine kinase 1 and 2 (SK1 and SK2), which catalyze the synthesis of S1P, may be useful anti- proliferative agents. We have synthesized a series of sphingosine-based inhibitors of SK and SK2. Also provided in this invention are compounds that activate SK1 which can be used in diseases such as fibrosis, where intracellular S1P is anti-fibrotic.
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AU2015330955A1 (en) | 2014-10-08 | 2017-05-25 | Central Adelaide Local Health Network Inc. | Modulators of 14-3-3 functionality and uses thereof |
WO2016085933A1 (en) | 2014-11-24 | 2016-06-02 | The Board Of Trustees Of The University Of Illinois | Method of preventing or treating a pulmonary disease or condition |
CN108366990B (en) | 2015-09-24 | 2021-09-03 | 加利福尼亚大学董事会 | Synthetic sphingolipid molecules, drugs, methods of their synthesis and methods of treatment |
JP6902040B2 (en) | 2016-01-28 | 2021-07-14 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | How to Increase the Efficacy of Immune Checkpoint Inhibitors |
US20170305861A1 (en) * | 2016-04-25 | 2017-10-26 | Immunomet Therapeutics, Inc | Heteroaryl compounds comprising nitrogen and use thereof |
WO2018035292A1 (en) * | 2016-08-18 | 2018-02-22 | Memorial Sloan Kettering Cancer Center | Inhibition of sphingosine l-phosphate receptor for treatment and prevention of lymphedema |
WO2019162325A1 (en) | 2018-02-21 | 2019-08-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of sk1 as biomarker for predicting response to immunecheckpoint inhibitors |
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2014
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