Structure-Activity Relationships for Itraconazole-Based Triazolone Analogues As Hedgehog Pathway Inhibitors

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2019 Mar 22

PMID 30896941

Citations 5

Authors

Jennifer R Pace

Kelly A Teske

Lianne Q Chau

Radha Charan Dash

Angela M Zaino

Robert J Wechsler-Reya

M Kyle Hadden

Affiliations

Soon will be listed here.

Abstract

The Food and Drug Administration-approved antifungal agent, itraconazole (ITZ), has been increasingly studied for its novel biological properties. In particular, ITZ inhibits the hedgehog (Hh) signaling pathway and has the potential to serve as an anticancer chemotherapeutic against several Hh-dependent malignancies. We have extended our studies on ITZ analogues as Hh pathway inhibitors through the design, synthesis, and evaluation of novel des-triazole ITZ analogues that incorporate modifications to the triazolone/side chain region of the scaffold. Our overall results suggest that the triazolone/side chain region can be replaced with various functionalities (hydrazine carboxamides and meta-substituted amides) resulting in improved potency when compared to ITZ. Our studies also indicate that the stereochemical orientation of the dioxolane ring is important for both potent Hh pathway inhibition and compound stability. Finally, our studies suggest that the ITZ scaffold can be successfully modified in terms of functionality and stereochemistry to further improve its anti-Hh potency and physicochemical properties.

Citing Articles

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Formulation and evaluation of itraconazole liposomes for Hedgehog pathway inhibition.

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Truncated Itraconazole Analogues Exhibiting Potent Anti-Hedgehog Activity and Improved Drug-like Properties.

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Development of posaconazole-based analogues as hedgehog signaling pathway inhibitors.

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