Manufacturing Development and Genotoxic Impurity Control Strategy of the Hedgehog Pathway Inhibitor Vismodegib

Angelaud, Rémy; Reynolds, Mark; Venkatramani, Cadapakam J.; Savage, Scott A.; Trafelet, Huldreich; Landmesser, Thomas; Demel, Peter; Levis, Michael; Ruha, Olivier; Rueckert, Baerbel; Jaeggi, Heinz

doi:10.1021/acs.oprd.6b00208

Cited by 28 publications

(23 citation statements)

References 16 publications

(7 reference statements)

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“…Amination of 18 and 19 afforded multiple aminated products through carboarene functionalization. After purification and/or derivatization, the antibiotic sulfamethoxazole and the anticancer agent vismodegib, respectively, are quickly accessible. In a hypothetical drug discovery scenario, our method provides access to aminated analogues of which the isomer with the best biological activity could then be identified.…”

Section: Figurementioning

confidence: 99%

Divergent Late‐Stage (Hetero)aryl C−H Amination by the Pyridinium Radical Cation

et al. 2018

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(Hetero)arylamines constitute some of the most prevalent functional molecules, especially as pharmaceuticals. However, structurally complex aromatics currently cannot be converted into arylamines, so instead, each product isomer must be assembled through a multistep synthesis from simpler building blocks. Herein, we describe a late‐stage aryl C−H amination reaction for the synthesis of complex primary arylamines that other reactions cannot access directly. We show and rationalize through a mechanistic analysis the reasons for the wide substrate scope and the constitutional diversity of the reaction, which gives access to molecules that would not have been readily available otherwise.

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Section: Figurementioning

confidence: 99%

Divergent Late‐Stage (Hetero)aryl C−H Amination by the Pyridinium Radical Cation

et al. 2018

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“…Vismodegib [1] is synthesized in a 4-step manufacturing process from two designated starting materials, 2-(2-chloro-5nitrophenyl)pyridineand 2-chloro-4-(methylsulfonyl)benzoic acid. During the course of these development vismodegib processes, four potential genotoxic impurities (GTIs) in the API introduced by the nitro starting material [4]. Such impurities may show cancer unwanted toxicity.…”

Section: Introductionmentioning

confidence: 99%

A Simple and Sensitive LC-MS/MS Method for Determination and Quantification of Potential Genotoxic Impurities in the Vismodegib Active Pharmaceutical Ingredient

Rao

Kumar

Vardhan

et al. 2021

JPRI

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A rapid and sensitive LC-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantitative analysis of four potential genotoxic impurities Imp-A (2-chloro-5-nitroaniline), Imp-B (1-chloro-2-iodo-4-nitrobenzene), Imp-C (1-(2-chloro-5-nitrophenyl)ethan-1-one) and Imp-D (2-chloro-5-nitrobenzoic acid) in Vismodegib API drug sample. This trace analysis was achieved on CSH C18, 15.0 cm x 3.0 mm, 1.7 micron column maintained at 45°C. Optimal mobile phase consisted of 0.05% formic acid in water was used as mobile phase A and acetonitrile used as mobile phase B in gradient mode with the flow rate of 0.5 mL/min. The developed method had the short run time of 12 minutes. Quantification of four potential genotoxic impurities were carried out using mass detection with electrospray ionization in multiple reaction monitoring mode. The method was linear in the range of 0.03 ppm to 1.50 ppm for four potential genotoxic impurities with a correlation coefficient not less than 0.999. The recoveries were found satisfactory over the range between 96.67 and 106.90% for all selected impurities. The developed method was able to quantitate all four PGIs at a concentration level of 0.03 ppm (0.03 ppm with respect to 20 mg /mL Vismodegib).

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“…Most Hh pathway inhibitors suppress the function of Smo receptor. To date, Vismodegib (1), Sonidegib (2) and Glasdegib (3) have been the Smo antagonists approved by the U.S. Food and Drug Administration (FDA) for the treatment of BCC and AML (Angelaud et al, 2016;Lindsley, 2016;Munchhof et al, 2012;Pan et al, 2010;Robarge et al, 2009;Sheridan, 2019) (Figure 1). Despite the significant accomplishment in the development of Hh pathway inhibitors, the clinical use of 1 and 2 is severely restricted by virtue of their several adverse effects including diarrhea, taste disturbance, hair loss, and muscle spasms (Ghirga et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Design and biological evaluation of phenyl imidazole analogs as hedgehog signaling pathway inhibitors

et al. 2020

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The hedgehog (Hh) signaling pathway is involved in diverse aspects of cellular events. Aberrant activation of Hh signaling pathway drives oncogenic transformation for a wide range of cancers, and it is therefore a promising target in cancer therapy. In the principle of association and ring-opening, we designed and synthesized a series of Hh signaling pathway inhibitors with phenyl imidazole scaffold, which were biologically evaluated in Gli-Luc reporter assay. Compound 25 was identified to possess high potency with nanomolar IC 50 , and moreover, it preserved the inhibition against wild-type and drug-resistant Smo-overexpressing cells. A molecular modeling study of compound 25 expounded its binding mode to Smo receptor, providing a basis for the further structural modification of phenyl imidazole analogs.

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Manufacturing Development and Genotoxic Impurity Control Strategy of the Hedgehog Pathway Inhibitor Vismodegib

Cited by 28 publications

References 16 publications

Divergent Late‐Stage (Hetero)aryl C−H Amination by the Pyridinium Radical Cation

Divergent Late‐Stage (Hetero)aryl C−H Amination by the Pyridinium Radical Cation

A Simple and Sensitive LC-MS/MS Method for Determination and Quantification of Potential Genotoxic Impurities in the Vismodegib Active Pharmaceutical Ingredient

Design and biological evaluation of phenyl imidazole analogs as hedgehog signaling pathway inhibitors

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