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

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Reeves EKM, Hoffman EP, Nagaraju K, Damsker JM, McCall JM

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

Bioorg Med Chem. 2013 Apr 15;21(8):2241-2249. doi: 10.1016/j.bmc.2013.02.009. Epub 2013 Feb 18.

PubMed ID
23498916 [ View in PubMed
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Abstract

Delta9,11 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 Delta9,11 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 Delta9,11 steroids showed novel anti-inflammatory properties, retaining NF-kappaB 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 Delta9,11 chemistry. Twenty Delta9,11 derivatives were tested in in vitro screens for NF-kappaB inhibition and GR translocation to the nucleus, and low cell toxicity. VBP15 was selected as the lead compound due to potent NF-kappaB 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.

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