期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 21, 期 8, 页码 2241-2249出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2013.02.009
关键词
Glucocorticoids; VBP15; Steroids; Anti-inflammatories; Neuromuscular disease
资金
- Congressionally Directed Medical Research Program of the US Department of Defense [W81XWH-09-1-0218, W81XWH-11-1-0754]
- Muscular Dystrophy Association
- Foundation to Eradicate Duchenne
- NIH Wellstone Muscular Dystrophy Research Center [1U54HD053177-01A1]
- NIH Therapeutics for Rare and Neglected Disease (TRND) program
Delta 9,11 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 Delta 9,11 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 Delta 9,11 steroids showed novel anti-inflammatory properties, retaining NF-kappa B 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 Delta 9,11 chemistry. Twenty Delta 9,11 derivatives were tested in in vitro screens for NF-kappa B inhibition and GR translocation to the nucleus, and low cell toxicity. VBP15 was selected as the lead compound due to potent NF-kappa B 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. (C) 2013 Elsevier Ltd. All rights reserved.
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