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

Abstract

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.

Cs2CO3-Promoted reaction of tertiary bromopropargylic alcohols and phenols in DMF: a novel approach to α-phenoxyketones

“…Among the approaches to produce α-phenoxyketones, the most common methodologies are base-catalyzed alkylation of the corresponding phenols with halo- [ 28 – 30 ] and mesyl [ 31 – 33 ] ketones ( Scheme 9 ), the preparation of which are not always selective and high-yielded. The ring opening of ArOCH 2 -epoxides [ 34 – 35 ], the SmI 2 -catalyzed reductive coupling of acid halides with ketones [ 36 – 37 ] and acetolyses of α-phenoxy-α-diazoketones [ 38 ] were also employed.…”

Antibody–Drug Conjugates for Immunology

“…As mentioned above, the described studies expand the growing application of antibody–drug conjugates in the immunology field. ,− The associated data provide additional examples of antibody-mediated delivery of glucocorticoid payloads as a means to minimize their often undesired systemic effects while retaining potent anti-inflammatory activity. The present study also illustrates the concept of arming an active anti-inflammatory mAb with such payloads as a means to further improve efficacy.…”

“…However, these agents can also cause musculoskeletal, endocrine, and gastrointestinal side effects, as well as other toxicities, that can limit their therapeutic usefulness (especially when administered chronically) . Accordingly, several research groups have previously explored the conjugation of glucocorticoids to antibodies as a means of reducing such unwanted systemic outcomes while preserving the desired anti-inflammatory activities of the attached molecules. − Hobson and co-workers extended these approaches by conjugating glucocorticoid payloads to an antibody that targets tumor necrosis factor-α (TNF). The membrane-bound form of TNF is frequently expressed on the surface of activated immune cells, and prior studies demonstrated that anti-TNF antibodies were internalized and trafficked to the lysosomal compartments of such cells following binding .…”

“…The public crystal structure of dexamethasone ( 1 ) bound to the glucocorticoid receptor (GR) was utilized to model numerous acetal-containing derivatives that were loosely derived from the active metabolite of ciclesonide (des-ciclesonide, 2 ; Figure ). A wide variety of different acetal moieties bearing diverse amine substituents were synthesized and tested as part of these activities (for a related modeling-based approach, see ref ). Fluorine substituents were also introduced at key locations in the glucocorticoid core that were known to improve anti-inflammatory activity.…”

Scaffold-Retained Structure Generator to Exhaustively Create Molecules in an Arbitrary Chemical Space

“…Accurate SARs may be obtained by comprehensively comparing side chains without changing the scaffold, which is the central backbone of the original molecule. Some of the latest research to identify anticancer drugs, − psychiatric drugs, , antivirus drugs, , and even antibody–drug conjugates , are based on SARs, which represent an indispensable important research method.…”