110931-77-6Relevant articles and documents
Development of posaconazole-based analogues as hedgehog signaling pathway inhibitors
Teske, Kelly A.,Dash, Radha Charan,Morel, Shana R.,Chau, Lianne Q.,Wechsler-Reya, Robert J.,Hadden, M. Kyle
, p. 320 - 332 (2019)
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.
NOVEL PYRIDAZONES AND TRIAZINONES FOR THE TREATMENT AND PROPHYLAXIS OF HEPATITIS B VIRUS INFECTION
-
Page/Page column 27-28, (2016/02/29)
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.
Racemic and chiral lactams as potent, selective and functionally active CCR4 antagonists
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.
, p. 5537 - 5542 (2007/10/03)
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.