Design and Validation of the First Family of Photo-Activatable Ligands for Melatonin Receptors

Somalo-Barranco, Gloria; Serra, Carme; Lyons, David; Piggins, Hugh D.; Jockers, Ralf; Llebaría, Amadeu

doi:10.1021/acs.jmedchem.2c00717

Cited by 8 publications

(4 citation statements)

References 52 publications

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“…The deprotection was originally performed with TFA in CH 2 Cl 2 , but significant acetal epimerization and incomplete conversion were observed. A screen quickly revealed that HBr in AcOH was a better alternative, , having both improved product formation and less acetal epimerization across several solvents. The product precipitates under these conditions, with CH 3 CN affording the best diastereoselectivity ratio (dr) and stability over time, likely due to low product solubility in this solvent (0.2 mg/mL).…”

Section: Resultsmentioning

confidence: 99%

Development and Execution of a Scalable Route to an Immunology ADC Drug-Linker for ABBV-154

Bennett,

Shen,

Gates

et al. 2024

Org. Process Res. Dev.

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Bromoacetamide 1 is a phosphorylated glucocorticoid drug-linker used in conjugation with the monoclonal antibody (mAb) adalimumab to produce the antibody-drug conjugate ABBV-154. A scalable route to drug-linker 1 has been developed that improves upon the first-generation sequence and allows the production of hundreds of grams of material. The new route begins with an acetal formation that incorporates a crystallization eliminating the previous need for reversed-phase chromatography to reject the undesired acetal diastereomer. The dipeptide portion of the linker fragment is then installed in a single transformation. The subsequent product is taken directly into a phosphorylation using a one-pot phosphoramidite displacement and oxidation sequence. Deprotection of a Fmoc group is accompanied by a continuous extraction to remove associated byproducts. The amine is coupled with bromoacetic acid, and a final global deprotection of three t-butyl groups with a reversed-phase purification yields drug-linker.

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Section: Resultsmentioning

confidence: 99%

Development and Execution of a Scalable Route to an Immunology ADC Drug-Linker for ABBV-154

Bennett,

Shen,

Gates

et al. 2024

Org. Process Res. Dev.

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“…Acetic acid imparted very little deprotection (entry 3). With 32 w/w% HBr in AcOH across several solvents, , the product was formed quickly with improved diastereoselectivity and precipitated (entries 4–7). We believe epimerization occurs primarily in the solution phase, and thus, precipitation limits ( S )-acetal formation.…”

Section: Resultsmentioning

confidence: 99%

Use of Impinging Jet to Improve Scalability in the Preparation of the ABBV-154 Drug-Linker

Bennett,

Mlinar,

Moschetta

et al. 2024

Org. Process Res. Dev.

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The final step in the preparation of the ABBV-154 drug-linker is a global acidic deprotection of three tert-butyl protecting groups that proceeds through several intermediates and is complicated by acetal epimerization, which generates an undesired diastereomer. This complex reaction was initially optimized in a batch setup, but scaling issues prompted the development of a flow process with an impinging jet mixing element. Initial studies utilized commercially available Y-mixers for small-scale experiments; however, clogging of the mixer was difficult to avoid. A three-dimensional (3D) printed Y-mixer impinging jet was created for lab development to avoid this issue and scale down the geometry of the plant-scale jet. The impinging process was executed in the manufacturing environment at kilogram scale, maintaining the desired diastereoselectivity, and reversed-phase chromatography enabled purification of the drug-linker. This paper discusses the key parameters examined to ensure successful scaleup of a mixing-sensitive reaction that demonstrated superior selectivity in flow compared to the batch process.

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“…Labeled subtype-specific ligands are highly desirable to determine the specific receptor present in cells and tissues naturally expressing the receptor(s). Outside of the strict domain of labelled compounds, recent studies reported the development of fluorescent ligands at melatonin receptors [80] as well as the synthesis of light-activatable caged melatonin compounds [81]. These molecules represent key elements in the toolbox for the pharmacological studies of melatonin receptors.…”

Section: Labeled Tracers For Melatonin Receptormentioning

confidence: 99%

Molecular Characterization and Pharmacology of Melatonin Receptors in Animals

2023

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Melatonin, the hormone of darkness, is secreted in minute amounts during the night and is virtually undetectable during the day. Melatonin mainly acts on high-affinity G protein-coupled receptors. The present review will trace the path of the discovery of melatonin receptors from their cloning, expression and purification to the development of recent radioactive and fluorescent tracers. We will then report on the state-of-the-art of melatonin receptor functional properties, including ligand bias and system bias due to receptor-associated proteins and receptor heteromers. Currently available antibodies raised against melatonin receptors will be critically reviewed here for the first time. The review will close with future perspectives in terms of the discovery of allosteric ligands and the in vivo validation of a range of melatonin receptor-associated signaling complexes to improve future drug development.

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Design and Validation of the First Family of Photo-Activatable Ligands for Melatonin Receptors

Cited by 8 publications

References 52 publications

Development and Execution of a Scalable Route to an Immunology ADC Drug-Linker for ABBV-154

Development and Execution of a Scalable Route to an Immunology ADC Drug-Linker for ABBV-154

Use of Impinging Jet to Improve Scalability in the Preparation of the ABBV-154 Drug-Linker

Molecular Characterization and Pharmacology of Melatonin Receptors in Animals

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