- Development of posaconazole-based analogues as hedgehog signaling pathway inhibitors
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Inhibition of the hedgehog (Hh) signaling pathway has been validated as a therapeutic strategy to treat basal cell carcinoma and holds potential for several other forms of human cancer. Itraconazole and posaconazole are clinically useful triazole anti-fungals that are being repurposed as anti-cancer agents based on their ability to inhibit the Hh pathway. We have previously demonstrated that removal of the triazole from itraconazole does not affect its ability to inhibit the Hh pathway while abolishing its primary side effect, potent inhibition of Cyp3A4. To develop structure-activity relationships for the related posaconazole scaffold, we synthesized and evaluated a series of des-triazole analogues designed through both ligand- and structure-based methods. These compounds demonstrated improved anti-Hh properties compared to posaconazole and enhanced stability without inhibiting Cyp3A4. In addition, we utilized a series of molecular dynamics and binding energy studies to probe specific interactions between the compounds and their proposed binding site on Smoothened. These studies strongly suggest that the tetrahydrofuran region of the scaffold projects out of the binding site and that π-π interactions between the compound and Smoothened play a key role in stabilizing the bound analogues.
- Teske, Kelly A.,Dash, Radha Charan,Morel, Shana R.,Chau, Lianne Q.,Wechsler-Reya, Robert J.,Hadden, M. Kyle
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Read Online
- A PROCESS FOR THE MANUFACTURE OF POSACONAZOLE
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The present invention discloses an improved process for the manufacture of Posaconazole, an anti-fungal agent belonging to the category of substituted Tetrahydrofuran Triazole compound. The present invention further describes preparation of formula A and formula B, the key intermediates in the preparation of Posaconazole. The invention also discloses novel intermediates that are useful in the synthesis of Posaconazole.
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Page/Page column 9; 23; 24
(2019/05/10)
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- Preparation method of posaconazole main ring
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The invention discloses a preparation method of a posaconazole main ring. The preparation method comprises steps as follows: 1), a compound F is dissolved in an organic solvent I, then thionyl chloride is added for reaction, and a compound G is obtained;
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Paragraph 0021
(2016/10/17)
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- NOVEL PYRIDAZONES AND TRIAZINONES FOR THE TREATMENT AND PROPHYLAXIS OF HEPATITIS B VIRUS INFECTION
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The invention provides novel compounds having the general formula wherein R1, R2, R3, X and a are as described in the description and in the claims, as well as or pharmaceutically acceptable salts thereof. The invention also contains compositions including the compounds and methods of using the compounds.
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Page/Page column 27-28
(2016/02/29)
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- Racemic and chiral lactams as potent, selective and functionally active CCR4 antagonists
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A series of racemic and chiral, nonracemic lactams that display high binding affinities, functional chemotaxis antagonism, and selectivity toward CCR4 are described. Compound 41, which provides reasonably high blood levels in mice when dosed intraperitoneally, was identified as a useful pharmacological tool to explore the role of CCR4 antagonism in animal models of allergic disease. A series of racemic and chiral, nonracemic lactams that display high binding affinities, functional chemotaxis antagonism, and selectivity toward CCR4 are described. Compound 41, which provides reasonably high blood levels in mice when dosed intraperitoneally, was identified as a useful pharmacological tool to explore the role of CCR4 antagonism in animal models of allergic disease.
- Newhouse, Bradley,Allen, Shelley,Fauber, Benjamin,Anderson, Aaron S.,Eary, C. Todd,Hansen, Joshua D.,Schiro, Justin,Gaudino, John J.,Laird, Ellen,Chantry, David,Eberhardt, Christine,Burgess, Laurence E.
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p. 5537 - 5542
(2007/10/03)
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- Concise asymmetric routes to 2,2,4-trisubstituted tetrahydrofurans via chiral titanium imide enolates: Key intermediates towards synthesis of highly active azole antifungals Sch 51048 and Sch 56592
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Two complimentary approaches to the key (-)-(2R)-cis-tosylate 1 and its (+)-(2S)-enantiomer 15 via generation of chiral imide enolates having a 2,2-disubstituted olefin functionality in the β-position, are described. In a 'protecting group free' sequence, reaction of the titanium enolate generated from (4R)-benzyl-2-oxazolidinone derived imide 5b with s-trioxane provided a convenient intermediate 19 which could be directly subjected to 2,4-diastereoselective iodocyclization.
- Saksena, Anil K.,Girijavallabhan, Viyyoor M.,Wang, Haiyan,Liu, Yi-Tsung,Pike, Russell E.,Ganguly, Ashit K.
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p. 5657 - 5660
(2007/10/03)
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- Synthesis and Structure-Activity Relationships of Naphthalene-Substituted Derivatives of the Allylamine Antimycotic Terbinafine
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Derivatives of the allylamine antimycotic terbinafine (1) with varied substitution at the naphthalene ring system have been prepared, and their antifungal activity has been evaluated.In general, the potency is strongly dependent on the bulkiness of the su
- Nussbaumer, Peter,Dorfstaetter, Gerhard,Leitner, Ingrid,Mraz, Karin,Vypel, Hermann,Stuetz, Anton
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p. 2810 - 2816
(2007/10/02)
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