title: 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.
authors.affiliation: ReveraGen BioPharma, Inc., 9700 Great Seneca Hwy Rockville, MD 20910, United States. Electronic address: erica.reeves@reveragen.com.
authors.forename: Erica K M
authors.initials: EKM
authors.lastname: Reeves
authors.affiliation: ReveraGen BioPharma, Inc., 9700 Great Seneca Hwy Rockville, MD 20910, United States; Center for Genetic Medicine Research, Children's National Medical Center, 111 Michigan Ave. NW, Washington, DC 20010, United States; Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC 20052, United States.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
authors.affiliation: ReveraGen BioPharma, Inc., 9700 Great Seneca Hwy Rockville, MD 20910, United States; Center for Genetic Medicine Research, Children's National Medical Center, 111 Michigan Ave. NW, Washington, DC 20010, United States; Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC 20052, United States.
authors.forename: Kanneboyina
authors.initials: K
authors.lastname: Nagaraju
authors.affiliation: ReveraGen BioPharma, Inc., 9700 Great Seneca Hwy Rockville, MD 20910, United States.
authors.forename: Jesse M
authors.initials: JM
authors.lastname: Damsker
authors.affiliation: ReveraGen BioPharma, Inc., 9700 Great Seneca Hwy Rockville, MD 20910, United States; PharMac, LLC, P.O. Box 2253, Boca Grande, FL 33921 United States.
authors.forename: John M
authors.initials: JM
authors.lastname: McCall
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D002467:Cell Nucleus / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005938:Glucocorticoids / Q000737:chemistry / Q000494:pharmacology; D000882:Haplorhini; D006801:Humans; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011244:Pregnadienediols / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats
chemical_list: D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D016328:NF-kappa B; D011244:Pregnadienediols; C418047:anecortave acetate