Discovery of pyrrolo[3,2-c]quinoline-4-one derivatives as novel hedgehog signaling inhibitors

Ohashi, Taiki; Oguro, Yuya; Tanaka, Toshio; Shiokawa, Zenyu; Shibata, Sachio; Sato, Yoshihiko; Yamakawa, Hiroko; Hattori, Harumi; Yamamoto, Yoshiyuki; Kondo, Shigeru; Miyamoto, Maki; Tojo, Hideaki; Baba, Atsuo; Sasaki, Satoshi

doi:10.1016/j.bmc.2012.07.039

Cited by 54 publications

(26 citation statements)

References 16 publications

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“…22,23 TAK-441 is soluble in most organic solvents and forms solvates with common solvents. Furthermore, TAK-441 anhydrous polymorphs showed enantiotropic relationships.…”

Section: ■ Introductionmentioning

confidence: 99%

Solid Form Selection of Highly Solvating TAK-441 Exhibiting Solvate-Trapping Polymorphism

Iwata

Kojima

Ikeda

2014

Crystal Growth & Design

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Solid form selection of active pharmaceutical ingredients is essential for pharmaceutical development. Solvates, except for hydrates, are rarely selected because of their physical instability and the potential toxicity of solvent. Here, the solid form selection of TAK-441, a highly solvating compound, was conducted. Anhydrate form I and 12 solvates were obtained from solution. The solvates showed isomorphism and could be placed into three categories. Anhydrate forms II, III, and IV were obtained via the desolvation of different type solvates, and anhydrate form V crystallized following thermal conversion of solvates. Equilibrium solubility analysis suggested that certain thermodynamic relationships between anhydrates were enantiotropic in nature. Moreover, form I was more stable than other polymorphs at ambient temperature, and was thus selected for further development. Finally, crystal structure analyses revealed that form I was an isomorphic desolvate of another solvate type (type 4), which immediately desolvated upon harvesting, and that TAK-441 crystallized only via solvate formation. Notably, types 2 and 3 solvates possessed unique channel structures, and pores of type 4 solvate were much larger than those of other types. This large pore size may cause extreme instability of type 4 solvate.

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“…22,23 TAK-441 is soluble in most organic solvents and forms solvates with common solvents. Furthermore, TAK-441 anhydrous polymorphs showed enantiotropic relationships.…”

Section: ■ Introductionmentioning

confidence: 99%

Solid Form Selection of Highly Solvating TAK-441 Exhibiting Solvate-Trapping Polymorphism

Iwata

Kojima

Ikeda

2014

Crystal Growth & Design

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“…7 Figure 3 illustrates our retrosynthetic analysis to access novel bicyclic cores with these two moieties. To construct the unique bicyclic core of 2, it was necessary to synthesize intermediate 4.…”

Section: Chemistrymentioning

confidence: 99%

“…1). 7,8 However, it was still unclear that exact role of the core skeleton including substituents at the 4-and 5-positions. Thus, we evaluated the modification of central core to confirm these properties and discovered new potent Hh signaling inhibitors with novel skeletons compared to that of 1.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of hedgehog signaling inhibitor with novel core system

Ohashi

Tanaka

Shiokawa

et al. 2015

Bioorganic & Medicinal Chemistry

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“…Through high‐throughput screening, researchers at Takeda discovered thieno[3,2‐c]quinoline‐4‐one 69 as a potent Hh inhibitor with an IC 50 value of 5.1 nM in Gli‐luc reporter assay. Replacement of the thieno[3,2‐c]quinoline‐4‐one moiety with a pyrrolo[3,2‐c]quinoline‐4‐one scaffold led to compound 70 with lower IC 50 value of 2.9 nM . However, both compounds 69 and 70 displayed low metabolic stability to mouse hepatic microsome ( 70 : clearance of 95 μL/min/mg).…”

Section: Hh Signaling Pathway Inhibitorsmentioning

confidence: 99%

Strategies to target the Hedgehog signaling pathway for cancer therapy

Xin

Cruz

et al. 2018

Medicinal Research Reviews

100

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Hedgehog (Hh) signaling is an essential pathway in the human body, and plays a major role in embryo development and tissue patterning. Constitutive activation of the Hh signaling pathway through sporadic mutations or other mechanisms is explicitly associated with cancer development and progression in various solid malignancies. Therefore, targeted inhibition of the Hh signaling pathway has emerged as an attractive and validated therapeutic strategy for the treatment of a wide range of cancers. Vismodegib, a first-in-class Hh signaling pathway inhibitor was approved by the US Food and Drug Administration in 2012, and sonidegib, another potent Hh pathway inhibitor, received FDA's approval in 2015 as a new treatment of locally advanced or metastatic basal cell carcinoma. The clinical success of vismodegib and sonidegib provided strong support for the development of Hh signaling pathway inhibitors via targeting the smoothened (Smo) receptor. Moreover, Hh signaling pathway inhibitors aimed to target proteins, which are downstream or upstream of Smo, have also been pursued based on the identification of additional therapeutic benefits. Recently, much progress has been made in Hh singling and inhibitors of this pathway. Herein, medicinal chemistry strategies, especially the structural optimization process of different classes of Hh inhibitors, are comprehensively summarized. Further therapeutic potentials and challenges are also discussed.

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Discovery of pyrrolo[3,2-c]quinoline-4-one derivatives as novel hedgehog signaling inhibitors

Cited by 54 publications

References 16 publications

Solid Form Selection of Highly Solvating TAK-441 Exhibiting Solvate-Trapping Polymorphism

Solid Form Selection of Highly Solvating TAK-441 Exhibiting Solvate-Trapping Polymorphism

Synthesis and evaluation of hedgehog signaling inhibitor with novel core system

Strategies to target the Hedgehog signaling pathway for cancer therapy

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