Novel glucocorticoid antedrugs possessing a 21-(γ-lactone) ring

Angell, Richard; Biggadike, Keith; Farrell, Rosanne M.; Flack, Stephen S.; Hancock, Ashley P.; Irving, Wendy R.; Lynn, Sean M.; Procopiou, Panayiotis A.

doi:10.1039/b200190j

Cited by 14 publications

(11 citation statements)

References 9 publications

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“…C 21 derivatives were derived as follows: budesonide ( P1 , IA), flumetasone (ID), triamcinolone acetonide (IE), and fluocinolone acetonide (IF) were commercially available. IB and IC were obtained from IE and IF, separately, by ketal exchange with butyraldehyde in the presence of perchloric acid (step i) …”

Section: Resultssupporting

confidence: 94%

Development of Novel Glucocorticoids for Use in Antibody–Drug Conjugates for the Treatment of Inflammatory Diseases

et al. 2021

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Glucocorticoids (GCs) are widely used to treat a variety of autoimmune and inflammatory diseases; however, systemic delivery of GCs is associated with side effects that affect essentially every organ system, reflecting the nearly ubiquitous expression of the glucocorticoid receptor (GR). Targeted delivery of GCs to diseased tissues using antibody-glucocorticoid conjugates (GC-ADCs) offers a therapeutic alternative to overcome these adverse effects. Herein, we describe novel classes of GCs that exhibited greater potency than dexamethasone and budesonide, a 100fold selectivity toward the GR over other nuclear receptors, and no in vitro safety liability in pharmacology assays (hERG, AMES) and that demonstrated a substantial reduction in tumor necrosis factor-α (TNF-α) release in mice challenged with lipopolysaccharide (LPS). The site-specific conjugated GC-ADCs via cathepsin-cleavable linkers were highly stable in plasma and specifically released GCs in antigen-positive cells, suggesting that these novel GCs can serve as ADC payloads to treat autoimmune and inflammatory diseases.

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Section: Resultssupporting

confidence: 94%

Development of Novel Glucocorticoids for Use in Antibody–Drug Conjugates for the Treatment of Inflammatory Diseases

et al. 2021

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“…5 The proposed bridging structure would not, at first sight, be expected to be very reactive. Indeed, this arrangement of atoms is apparently stable at room temperature in water and in brine, as noted (46). However, within rC 552 , it appears to be quite reactive and can be converted to p572, as noted above.…”

Section: Crystallographic Characterization Of Rc 552mentioning

confidence: 61%

Cytochrome rC₅₅₂, Formed during Expression of the Truncated, Thermus thermophilus Cytochrome c₅₅₂ Gene in the Cytoplasm of Escherichia coli, Reacts Spontaneously To Form Protein-Bound 2-Formyl-4-vinyl (Spirographis) Heme^,

et al. 2004

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Expression of the truncated (lacking an N-terminal signal sequence) structural gene of Thermus thermophilus cytochrome c(552) in the cytoplasm of Escherichia coli yields both dimeric (rC(557)) and monomeric (rC(552)) cytochrome c-like proteins [Keightley, J. A., et al. (1998) J. Biol. Chem. 273, 12006-12016], which form spontaneously without the involvement of cytochrome c maturation factors. Cytochrome rC(557) is comprised of a dimer and has been structurally characterized [McRee, D., et al. (2001) J. Biol. Chem. 276, 6537-6544]. Unexpectedly, the monomeric rC(552) transforms spontaneously to a cytochrome-like chromophore having, in its reduced state, the Q(oo) transition (alpha-band) at 572 nm (therefore called p572). The X-ray crystallographic structure of rC(552), at 1.41 A resolution, shows that the 2-vinyl group of heme ring I is converted to a [heme-CO-CH(2)-S-CH(2)-C(alpha)] conjugate with cysteine 11. Electron density maps obtained from isomorphous crystals of p572 at 1.61 A resolution reveal that the 2-vinyl group has been oxidized to a formyl group. This explains the lower energy of the Q(oo)() transition, the presence of a new, high-frequency band in the resonance Raman spectra at 1666 cm(-1) for oxidized and at 1646 cm(-1) for reduced samples, and the greatly altered, paramagnetically shifted (1)H NMR spectrum observed for this species. The overall process defines a novel mechanism for oxidation of the 2-vinyl group to a 2-formyl group and adds to the surprising array of chemical reactions that occur in the interaction of heme with the CXXCH sequence motif in apocytochromes c.

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“…Direct synthesis of this impurity from the drug substance was considered reasonable, as per Scheme . However, the attempted selective hydrogenation of clobetasone 17-butyrate using water-wet 5% palladium on charcoal and cyclohexene as a hydrogen source failed.…”

Section: Discussionmentioning

confidence: 99%

Synthesis and Characterisation of Impurities of Manufacture in Support of Certificate of the European Pharmacopoeia Applications Part 1 (Clobetasone Butyrate)

Mcghie

Sewell

Devlin

et al. 2003

Org. Process Res. Dev.

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Established pharmaceutical products often have complex supply chains and regulatory histories. In Europe the European Directorate for the Quality of Medicine (EDQM) (information from European Pharmacopoeia website, http://www.pheur.org/) have promoted the use of certificates of suitability of the European Pharmacopoeia to ensure the quality of medicines by a commonly recognised set of standards, allowing the free movement of medicinal products in member states. This contribution describes the analytical and synthetic chemistry required to synthesise the impurities of manufacture of clobetasone butyrate.

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Novel glucocorticoid antedrugs possessing a 21-(γ-lactone) ring

Abstract: A series of novel pregnane derivatives bearing γ-butyrolactones at C21 were prepared and tested as glucocorticoid agonists. The compounds were also tested for their lability in human plasma, and found to be rapidly hydrolysed by the enzyme paraoxonase to the respective hydroxyacids.

Cited by 14 publications

References 9 publications

Development of Novel Glucocorticoids for Use in Antibody–Drug Conjugates for the Treatment of Inflammatory Diseases

Development of Novel Glucocorticoids for Use in Antibody–Drug Conjugates for the Treatment of Inflammatory Diseases

Cytochrome rC₅₅₂, Formed during Expression of the Truncated, Thermus thermophilus Cytochrome c₅₅₂ Gene in the Cytoplasm of Escherichia coli, Reacts Spontaneously To Form Protein-Bound 2-Formyl-4-vinyl (Spirographis) Heme^,

Synthesis and Characterisation of Impurities of Manufacture in Support of Certificate of the European Pharmacopoeia Applications Part 1 (Clobetasone Butyrate)

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Novel glucocorticoid antedrugs possessing a 21-(γ-lactone) ring

Abstract: A series of novel pregnane derivatives bearing γ-butyrolactones at C21 were prepared and tested as glucocorticoid agonists. The compounds were also tested for their lability in human plasma, and found to be rapidly hydrolysed by the enzyme paraoxonase to the respective hydroxyacids.

Cited by 14 publications

References 9 publications

Development of Novel Glucocorticoids for Use in Antibody–Drug Conjugates for the Treatment of Inflammatory Diseases

Development of Novel Glucocorticoids for Use in Antibody–Drug Conjugates for the Treatment of Inflammatory Diseases

Cytochrome rC552, Formed during Expression of the Truncated, Thermus thermophilus Cytochrome c552 Gene in the Cytoplasm of Escherichia coli, Reacts Spontaneously To Form Protein-Bound 2-Formyl-4-vinyl (Spirographis) Heme,

Synthesis and Characterisation of Impurities of Manufacture in Support of Certificate of the European Pharmacopoeia Applications Part 1 (Clobetasone Butyrate)

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Cytochrome rC₅₅₂, Formed during Expression of the Truncated, Thermus thermophilus Cytochrome c₅₅₂ Gene in the Cytoplasm of Escherichia coli, Reacts Spontaneously To Form Protein-Bound 2-Formyl-4-vinyl (Spirographis) Heme^,