- A Conformational Restriction Strategy for the Identification of a Highly Selective Pyrimido-pyrrolo-oxazine mTOR Inhibitor
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The mechanistic target of rapamycin (mTOR) plays a pivotal role in growth and tumor progression and is an attractive target for cancer treatment. ATP-competitive mTOR kinase inhibitors (TORKi) have the potential to overcome limitations of rapamycin derivatives in a wide range of malignancies. Herein, we exploit a conformational restriction approach to explore a novel chemical space for the generation of TORKi. Structure-activity relationship (SAR) studies led to the identification of compound 12b with a ～450-fold selectivity for mTOR over class I PI3K isoforms. Pharmacokinetic studies in male Sprague Dawley rats highlighted a good exposure after oral dosing and a minimum brain penetration. CYP450 reactive phenotyping pointed out the high metabolic stability of 12b. These results identify the tricyclic pyrimido-pyrrolo-oxazine moiety as a novel scaffold for the development of highly selective mTOR inhibitors for cancer treatment.
- Borsari, Chiara,Rageot, Denise,Dall'Asen, Alix,Bohnacker, Thomas,Melone, Anna,Sele, Alexander M.,Jackson, Eileen,Langlois, Jean-Baptiste,Beaufils, Florent,Hebeisen, Paul,Fabbro, Doriano,Hillmann, Petra,Wymann, Matthias P.
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p. 8609 - 8630
(2019/10/16)
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- Fused Thiazole Derivatives As Kinase Inhibitors
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A series of 6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-4(5H)-one derivatives, which are substituted in the 2-position by a substituted morpholin-4-yl moiety, being selective inhibitors of PI3 kinase enzymes, are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive or ophthalmic conditions.
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Page/Page column 11
(2011/01/12)
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- FUSED THIAZOLE AND THIOPHENE DERIVATIVES AS KINASE INHIBITORS
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A series of fused bicyclic thiazole and thiophene derivatives which are substituted in the 2-position by an optionally substituted morpholin-4-yl moiety, and in the 4-position by hydroxy, oxo or an amine moiety, being selective inhibitors of PI3 kinase enzymes, are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive or ophthalmic conditions. (I)
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Page/Page column 110
(2009/07/17)
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- THIAZOLE DERIVATIVES AS KINASE INHIBITORS
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A series of thiazole derivatives which are substituted in the 2-position by a substituted morpholin-4-yl moiety, being selective inhibitors of P13 kinase enzymes, are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive or ophthalmic conditions.
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Page/Page column 40-41
(2008/12/05)
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- FUSED THIAZOLE DERIVATIVES AS KINASE INHIBITORS
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A series of 6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-4(5H)-one derivatives, which are substituted in the 2-position by a substituted morpholin-4-yl moiety, being selective inhibitors of PI3 kinase enzymes, are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive or ophthalmic conditions.
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Page/Page column 29
(2009/03/07)
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- 2-AMINOBENZOXAZOLE CARBOXAMIDES AS 5HT3 MODULATORS
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Compounds of formulae I, II and III: are disclosed as 5-HT3 inhibitors. The compounds are useful in treating CINV, IBS-D and other diseases and conditions.
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Page/Page column 31
(2008/12/04)
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- FUSED THIAZOLE DERIVATIVES AS KINASE INHIBITORS
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A series of 5,6-dihydro-l,3-benzothiazol-7(4H)-one derivatives, and analogues thereof, which are substituted in the 2-position by an optionally substituted morpholin-4-yl moiety, being selective inhibitors of PD kinase enzymes, are accordingly of b.enefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive or ophthalmic conditions.
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Page/Page column 77-78
(2008/06/13)
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- Chiral Synthesis of 3-Substituted Morpholines via Serine Enantiomers and Reductions of 5-Oxomorpholine-3-carboxylates
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The chiral synthesis of 3-hydroxymethyl- and 3-carboxy-morpholines from serine enantiomers is described.Chemoselective and total reductions of 5-oxomorpholine-3-carboxylates are key synthetic steps.
- Brown, George R.,Foubister, Alan J.,Wright, Brian
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p. 2577 - 2580
(2007/10/02)
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