VBP15: Preclinical characterization of a novel anti-inflammatory delta 9,11 steroid

Abstract

Δ9,11 modifications of glucocorticoids (21-aminosteroids) have been developed as drugs for protection against cell damage (lipid peroxidation; lazaroids) and inhibition of neovascularization (anecortave). Part of the rationale for developing these compounds has been the loss of glucocorticoid receptor binding due to the Δ9,11 modification, thus avoiding many immunosuppressive activities and deleterious side effect profiles associated with binding to glucocorticoid and mineralocorticoid receptors. We recently demonstrated that anecortave acetate and its 21-hydroxy analog (VBP1) do, in fact, show glucocorticoid and mineralocorticoid receptor binding activities, with potent translocation of the glucocorticoid receptor to the cell nucleus. We concluded that Δ9,11 steroids showed novel anti-inflammatory properties, retaining NF-κB inhibition, but losing deleterious glucocorticoid side effect profiles. Evidence for this was developed in pre-clinical trials of chronic muscle inflammation. Here, we describe a drug development program aimed at optimizing the Δ9,11 chemistry. Twenty Δ9,11 derivatives were tested in in vitro screens for NF-κB inhibition and GR translocation to the nucleus, and low cell toxicity. VBP15 was selected as the lead compound due to potent NF-κB inhibition and GR translocation similar to prednisone and dexamethasone, lack of transactivation properties, and good bioavailability. Phamacokinetics were similar to traditional glucocorticoid drugs with terminal half-life of 0.35 h (mice), 0.58 h (rats), 5.42 h (dogs), and bioavailability of 74.5% (mice), and 53.2% (dogs). Metabolic stability showed ≥80% remaining at 1 h of VBP6 and VBP15 in human, dog, and monkey liver microsomes. Solubility, permeability and plasma protein binding were within acceptable limits. VBP15 moderately induced CYP3A4 across the three human hepatocyte donors (24–42%), similar to other steroids. VBP15 is currently under development for treatment of Duchenne muscular dystrophy.

Phase 1 trial of vamorolone, a first-in-class steroid, shows improvements in side effects via biomarkers bridged to clinical outcomes

“…VBP-15 (generic name vamorolone) was developed as a dissociative steroid by synthesizing a series of compounds with a Δ9,11 steroidal scaffold, and testing of cell-based assays for retention of non-genomic anti-inflammatory activity (inhibition of TNF-induced NFκB activation; suppression of innate immunity pathways), and loss of genomic activity (GRE-mediated transcriptional reporters) [14,15]. Pre-clinical data has shown that vamorolone has potent binding to the glucocorticoid receptor and anti-inflammatory effects similar to traditional glucocorticoid drugs [15].…”

Lazaroid U-74389G inhibits the osteoblastic differentiation of IL-1β-indcued aortic valve interstitial cells through glucocorticoid receptor and inhibition of NF-κB pathway

“…Studies have suggested that these anti-inflammatory effects of this class of drugs may be mediated by the inhibition of the anti-inflammatory NF-kB activity [15,16]. Recently, the NF-kB inhibitory activity of two 21-aminosteroids, anecortave and VBP15, were found to be dependent on binding to the glucocorticoid receptor, contrary to previous models of the mechanism of action of this class of drugs [14,17,18]. We sought to determine if the clinically developed 21-aminosteroid, lazaroid U-74389G, also showed GR-dependent NF-kB inhibitory activity, and if this drug inhibited osteoblastic differentiation in AVICs.…”

VBP15, a novel dissociative steroid compound, reduces NFκB-induced expression of inflammatory cytokines in vitro and symptoms of murine trinitrobenzene sulfonic acid-induced colitis

“…VBP15 is an anti-inflammatory compound that has been shown to be an effective inhibitor of NFjB activity both in vitro and in vivo [19][20][21][22] but does not induce the GREmediated transcription (genomic transactivation property) believed to be responsible for many of the detrimental metabolic side effects of glucocorticoids [19,21]. In the current study, VBP15 inhibited the production of pro-inflammatory cytokines IL-6 and IL-8, as well as chemokine, CCL5, in TNFa-stimulated human intestinal epithelial cells.…”

“…Having previously shown that VBP15 reduces NFjB activity in vitro in muscle cells, lung cells, splenocytes, and macrophages [19][20][21][22], we sought to determine if VBP15 could reduce the expression of pro-inflammatory NFjBregulated cytokines in human intestinal epithelial cells. We treated intestinal epithelial cells for 24 h with VBP15 (10 lM), prednisolone (10 lM), or vehicle control (DMSO) and subsequently stimulated them with TNFa for an additional 24 h. Focusing on three cytokines (CCL5, IL-6 and IL-8) that are important in the pathogenesis of IBD, we found that VBP15 treatment significantly reduced the expression of all three by at least 68 %, and to a similar degree to that observed with prednisolone (Fig.…”

“…VBP15 is a novel anti-inflammatory drug, based on the lazaroid steroidal backbone, that optimizes the balance between transrepression (cytosolic NFjB inhibition) and transactivation (dimerized GR nuclear-translocation and subsequent genomic effects) [19] (Fig. 1).…”