Structural, Thermodynamic, and Kinetic Aspects of the Polymorphism and Pseudopolymorphism of Prednisolone (11,17α,21-Trihydroxy-1,4-pregnadien-3,20-dion)

Background Glucocorticoid drugs are highly effective anti-inflammatory agents, but chronic use is associated with extensive pharmacodynamic safety concerns that have a considerable negative impact on patient quality of life. Purpose Vamorolone (VBP15) is a first-in-class steroidal multi-functional drug that shows potent inhibition of pro-inflammatory NFkB pathways via high-affinity binding to the glucocorticoid receptor, high affinity antagonism for the mineralocorticoid receptor, and membrane stabilization properties. Pre-clinical data in multiple mouse models of inflammation showed retention of anti-inflammatory efficacy, but loss of most or all side effects. Experimental approach We report first-in-human Phase 1 clinical trials (86 healthy adult males), with single ascending doses (0.1–20.0 mg/kg), and multiple ascending doses (1.0–20 mg/kg/day; 14 days treatment). Key results Vamorolone was well-tolerated at all dose levels. Vamorolone showed pharmacokinetic and metabolism profiles similar to prednisone. Biomarker studies showed loss of side effects of traditional glucocorticoid drugs (bone fragility, metabolic disturbance, immune suppression). Suppression of the adrenal axis was 10-fold less than prednisone. The crystallographic structure of vamorolone was solved, and compared to prednisone and dexamethasone. There was overlap in structure, but differences in conformation at the C-ring where glucocorticoids interact with Asn564 of the glucocorticoid receptor. The predicted loss of Asn564 binding to vamorolone may underlie the loss of gene transcriptional activity. Conclusions and interpretations Vamorolone is a dissociative steroid that retains high affinity binding and nuclear translocation of both glucocorticoid (agonist) and mineralocorticoid (antagonist) receptors, but does not show pharmacodynamic safety concerns of existing glucocorticoid drugs at up to 20 mg/kg/day.

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“…The crystal structure of vamorolone was overlaid to previously reported crystal structures of prednisone and dexamethasone [32] (Fig. 6).…”

Section: Resultsmentioning

confidence: 99%

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

Hoffman

Riddle²,

Siegler

et al. 2018

Steroids

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“…Section C; Linden (2011). Some recent publications of ours on the same theme include Hopf et al (2012), Jones et al (2011), Nä ther & Jess (2006, Suitchmezian et al (2008Suitchmezian et al ( , 2011.…”

Section: Introductionmentioning

confidence: 93%

Thermodynamic and structural relationships between the two polymorphs of 1,3-dimethylurea

Näther¹,

Döring²,

Jeß³

et al. 2012

Acta Crystallogr Sect B

Self Cite

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The title compound exists as polymorph (I), Fdd2 with Z = 8 [Pérez‐Folch et al. (1997). J. Chem. Cryst.27, 367–369; Marsh (2004). Acta Cryst. B60, 252–253], and as polymorph (II), P21212 with Z = 2 [Martins et al. (2009). J. Phys. Chem. A, 113, 5998–6003]. We have redetermined both structures at somewhat lower temperatures [(I) at 180 K rather than room temperature; (II) at 100 K rather than 150 K]. For polymorph (I) the space group Fdd2 is confirmed rather than the original choice of Cc. The molecular structures of both polymorphs are essentially identical, with exact crystallographic twofold symmetry, approximate C2v symmetry, and a trans orientation of the H—N—C=O moiety. In both polymorphs the molecules associate into chains of rings with graph set C(4)[R21(6)] via bifurcated hydrogen‐bond systems C(N—H)2...O=C. In the polar structure (I) the chains are necessarily all parallel, whereas in (II) equal numbers of parallel and antiparallel chains are present. Further physical investigations [differential scanning calorimetry (DSC), powder investigations, solvent‐induced phase conversions] were undertaken: these showed: (i) that the commercially available compound consists predominantly of polymorph (II), which on heating transforms into polymorph (I) by an endothermic reaction, so that both polymorphs are related by enantiotropism; (ii) that polymorph (I) represents the more stable modification at room temperature, where polymorph (II) is metastable, with the thermodynamic transition temperature lying somewhere between 253 K and room temperature. An apparent third polymorph, consisting of fibrous needles, was shown by powder diffraction to consist of a mixture of polymorphs (I) and (II).

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“…The title compound (Dekker, 1980;Stroud et al, 1980) was obtained by degradation of solid prednisolone sodium phosphate at 373 K for 72 h, then extracted and isolated using HSCCC followed by preparative HPLC. Finally, the crystals were prepared by slow evaporation of the solvent from a saturated solution in methanol/acetone/H 2 O at room temperature (Suitschmezian et al, 2008).…”

Section: S2 Experimentalmentioning

confidence: 99%

11,20-Dihydroxy-3-oxopregna-1,4-dien-21-oic acid monohydrate

2011

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The title compound, C21H28O5·H2O, is the hydrate of a steroid derivative and was obtained by degradation of solid prednisolone sodium phosphate. The six C atoms in ring A are nearly co-planar with a mean deviation of 0.015 Å. Rings B and C are both in chair conformations, while ring D has an envelope form. In the crystal, intermolecular O—H⋯O hydrogen-bonding interactions occur between the hydroxy groups, carbonyl O atoms and solvent water molecules, resulting in an overall three-dimensional structure.

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Structural, Thermodynamic, and Kinetic Aspects of the Polymorphism and Pseudopolymorphism of Prednisolone (11,17α,21-Trihydroxy-1,4-pregnadien-3,20-dion)

Cited by 29 publications

References 54 publications

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

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

Thermodynamic and structural relationships between the two polymorphs of 1,3-dimethylurea

11,20-Dihydroxy-3-oxopregna-1,4-dien-21-oic acid monohydrate

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