Novel ketal ligands for the glucocorticoid receptor: in vitro and in vivo activity
Cameron J. SmithAmjad AliJames M. BalkovecDonald W. GrahamMilton L. HammondGool F. PatelGregory P. RouenScott K. SmithJames R. TataMonica EinsteinLan GeG. S. HarrisTheresa M. KellyPaul MazurChris M. ThompsonChuanlin F. WangJoanne M. WilliamsonDouglas K. MillerShilpa PanditJoseph C. SantoroAyesha SitlaniTing-ting D. YaminEdward A. O’NeillDennis M. ZallerEster Carballo‐JaneMichael J. ForrestSilvi Luell
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Inhaled and intranasal glucocorticoids are the most common and effective drugs for controlling symptoms and airway inflammation in respiratory diseases such as asthma, allergic rhinitis, and nasal polyposis. The last few years have seen a growing understanding of the mechanisms of glucocorticoid action and, in particular, the receptor that mediates glucocorticoid actions, the glucocorticoid receptor (GR). In this revision we present an update on the GR gene, the expression and regulation of its gene products, namely GR α and GR β , as well as their alterations in pathological states. GR α is responsible for the induction and repression of target genes, it is expressed in virtually all human cells and tissues, and its expression is known to be downregulated by glucocorticoids. GR β has been found to act as a dominant negative inhibitor of GR α ‐mediated transactivation in in vitro studies with transfected cells, but it does not appear to have a significant inhibitory effect on GR α ‐mediated transrepression. In addition, for most tissues the expression of GR β , at least at the mRNA level, is extremely low compared with that of GR α . Some pro‐inflammatory cytokines appear to upregulate the expression of GR β , and increased GR β expression has been reported in diseases associated with glucocorticoid resistance or insensitivity, such as bronchial asthma, nasal polyposis, and ulcerative colitis. However, the possible role of GR β in modulating glucocorticoid sensitivity and/or resistance in vivo has been highly debated and it is not yet clear.
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The tetrahydronaphthalene-benzoxazine glucocorticoid receptor (GR) partial agonist 4b was optimized to produce potent full agonists of GR. Aromatic ring substitution of the tetrahydronaphthalene leads to weak GR antagonists. Discovery of an "agonist trigger" substituent on the saturated ring of the tetrahydronaphthalene leads to increased potency and efficacious GR agonism. These compounds are efficacy selective in an NFkB GR agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing transactivation effects). 52 and 60 have NFkB pIC(50) = 8.92 (105%) and 8.69 (92%) and MMTV pEC(50) = 8.20 (47%) and 7.75 (39%), respectively. The impact of the trigger substituent on agonism is modeled within GR and discussed. 36, 52, and 60 have anti-inflammatory activity in a mouse model of inflammation after topical dosing with 52 and 60, having an effect similar to that of dexamethasone. The original lead was discovered by a manual agreement docking method, and automation of this method is also described.
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International asthma guidelines recommend that inhaled glucocorticoids be used as a monotherapy in all patients with mild to moderate disease because of their ability to suppress airways inflammation. Current evidence suggests that the therapeutic benefit of glucocorticoids is due to the transactivation and transrepression of anti-inflammatory and pro-inflammatory genes respectively. However, the extent to which clinically relevant glucocorticoids are equivalent in their ability to modulate gene expression is unclear.
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Glucocorticoids are well known for their potent anti-inflammatory and immunosuppressive actions. However, due to their potential to induce serious undesired effects, there is a great need for compounds with a better therapeutic index. Recent discoveries have demonstrated that the positive and negative regulation of gene expression via the glucocorticoid receptor is mediated by different mechanisms. This regulation is predominantly responsible for either anti-inflammatory effects or certain side effects, depending on whether it is negative or positive. Compounds that preferentially induce transrepression rather than transactivation should be superior to classical glucocorticoids. Indeed, proof of concept has been recently achieved with such selective glucocorticoid receptor agonists.
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A novel series of selective ligands for the human glucocorticoid receptor (hGR) are described. Preliminary structure-activity relationships were focused on substitution at C-1 and indicated a preference for 3-, 4-, and 5-substituted aromatic and benzylic groups. The resulting analogues, e.g., 18 and 34, exhibited excellent affinity for hGR (IC(50) 1.9 nM and 2.8 nM, respectively) and an interesting partial agonist profile in functional assays of transactivation (tyrosine aminotransferase, TAT, and glutamine synthetase, GS) and transrepression (IL-6). The most potent compounds described in this study were the tertiary alcohol derivatives 21 and 25. These candidates showed highly efficacious IL-6 inhibition versus dexamethasone. The thiophenyl analogue 25 was evaluated in vivo in the mouse LPS challenge model and showed an ED(50) = 4.0 mg/kg, compared to 0.5 mg/kg for prednisolone in the same assay.
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