Title:
SELECTIVE INHIBITORS AND ALLOSTERIC ACTIVATORS OF SPHINGOSINE KINASE
Document Type and Number:
WIPO Patent Application WO/2014/118556
Kind Code:
A3
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.
Inventors:
BITTMAN ROBERT (US)
PYNE NIGEL J (GB)
PYNE SUSAN (GB)
BAEK DONG JAE (US)
LIU ZHENG (US)
BYUN HOE SUP (US)
PYNE NIGEL J (GB)
PYNE SUSAN (GB)
BAEK DONG JAE (US)
LIU ZHENG (US)
BYUN HOE SUP (US)
Application Number:
PCT/GB2014/050264
Publication Date:
September 25, 2014
Filing Date:
January 31, 2014
Export Citation:
Assignee:
UNIV CITY NEW YORK RES FOUND (US)
UNIV STRATHCLYDE (GB)
BITTMAN ROBERT (US)
PYNE NIGEL J (GB)
PYNE SUSAN (GB)
BAEK DONG JAE (US)
LIU ZHENG (US)
BYUN HOE SUP (US)
UNIV STRATHCLYDE (GB)
BITTMAN ROBERT (US)
PYNE NIGEL J (GB)
PYNE SUSAN (GB)
BAEK DONG JAE (US)
LIU ZHENG (US)
BYUN HOE SUP (US)
International Classes:
C07D401/04; C07C215/08; C07C275/28; C07C275/30; C07C335/16; C07D207/08; C07D211/14; C07D211/46; C07D249/06; C07D295/03; C07D295/037; C07D295/088; C07D295/096; C07D307/14; C07F9/38
Domestic Patent References:
| WO2011016033A1 | 2011-02-10 | |||
| WO2001094357A1 | 2001-12-13 | |||
| WO2013049280A2 | 2013-04-04 |
Foreign References:
| US6107520A | 2000-08-22 | |||
| JPH0193562A | 1989-04-12 |
Other References:
DAVID MORMENEO ET AL: "Synthesis and preliminary antifungal evaluation of a library of phytosphingolipid analogues", ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 5, no. 23, 1 January 2007 (2007-01-01), pages 3769, XP055090185, ISSN: 1477-0520, DOI: 10.1039/b709421c
KOKATLA H P ET AL: "Stereoselective synthesis of safingol and its natural stereoisomer from d-glycals", TETRAHEDRON LETTERS, PERGAMON, GB, vol. 49, no. 32, 4 August 2008 (2008-08-04), pages 4728 - 4730, XP022776730, ISSN: 0040-4039, [retrieved on 20080613], DOI: 10.1016/J.TETLET.2008.05.112
LHERBET C ET AL: "Probing the stereochmistry of the active site of gamma-glutamyl transpeptidase using sulfur derivatives of L-glutamic acid", ORGANIC & BIOMOLECULAR CHEMISTRY, ROYAL SOCIETY OF CHEMISTRY, GB, vol. 2, no. 2, 1 January 2004 (2004-01-01), pages 238 - 245, XP003013855, ISSN: 1477-0520, DOI: 10.1039/B310767A
BENJAMIN WEISS ET AL: "II. Synthesis of Long Chain Fatty Acid Amines of Sphingosine and Dihydrosphingosine 1", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 80, no. 17, 1 September 1958 (1958-09-01), pages 4657 - 4658, XP055115001, ISSN: 0002-7863, DOI: 10.1021/ja01550a061
HOE-SUP BYUN ET AL: "Novel sphingosine-containing analogues selectively inhibit sphingosine kinase (SK) isozymes, induce SK1 proteasomal degradation and reduce DNA synthesis in human pulmonary arterial smooth muscle cells", MEDCHEMCOMM, vol. 4, no. 10, 6 August 2013 (2013-08-06), pages 1394, XP055115004, ISSN: 2040-2503, DOI: 10.1039/c3md00201b
KOKATLA H P ET AL: "Stereoselective synthesis of safingol and its natural stereoisomer from d-glycals", TETRAHEDRON LETTERS, PERGAMON, GB, vol. 49, no. 32, 4 August 2008 (2008-08-04), pages 4728 - 4730, XP022776730, ISSN: 0040-4039, [retrieved on 20080613], DOI: 10.1016/J.TETLET.2008.05.112
LHERBET C ET AL: "Probing the stereochmistry of the active site of gamma-glutamyl transpeptidase using sulfur derivatives of L-glutamic acid", ORGANIC & BIOMOLECULAR CHEMISTRY, ROYAL SOCIETY OF CHEMISTRY, GB, vol. 2, no. 2, 1 January 2004 (2004-01-01), pages 238 - 245, XP003013855, ISSN: 1477-0520, DOI: 10.1039/B310767A
BENJAMIN WEISS ET AL: "II. Synthesis of Long Chain Fatty Acid Amines of Sphingosine and Dihydrosphingosine 1", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 80, no. 17, 1 September 1958 (1958-09-01), pages 4657 - 4658, XP055115001, ISSN: 0002-7863, DOI: 10.1021/ja01550a061
HOE-SUP BYUN ET AL: "Novel sphingosine-containing analogues selectively inhibit sphingosine kinase (SK) isozymes, induce SK1 proteasomal degradation and reduce DNA synthesis in human pulmonary arterial smooth muscle cells", MEDCHEMCOMM, vol. 4, no. 10, 6 August 2013 (2013-08-06), pages 1394, XP055115004, ISSN: 2040-2503, DOI: 10.1039/c3md00201b
Attorney, Agent or Firm:
CHAPMAN, Paul (Atholl Exchange6 Canning Street,Edinburgh, EH3 8EG, GB)
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