Non-steroidal Glucocorticoid Receptor Agonists Research Articles

Impact of atropisomerism on a non-steroidal glucocorticoid receptor agonist.

To investigate atropisomers of non-steroidal glucocorticoid receptor modulator GSK866, a virtual library of substituted benzoic acid analogues was enumerated. Compounds from this library were subjected to a torsion angle scan using Spartan'20 to calculate the torsion rotation energy barrier which identified compounds predicted to be stable as atropisomers. After synthesis of the library, analysis showed that compounds 13 and 14 existed as stable atropisomers 13a, 13b, 14a and 14b, in agreement with the earlier calculations. Screening in a glucocorticoid receptor cellular assay showed that one compound from each atropisomer pair was significantly more potent than the other. Docking in a public structure of the glucocorticoid receptor (PBD code 3E7C) enabled the stereochemistry of the two most potent compounds 13a and 14b to be assigned as (R a) and (S a), respectively.

Characterization of a novel non-steroidal glucocorticoid receptor agonist optimized for topical treatment

Glucocorticoids (GCs) are commonly used topical treatments for skin diseases but are associated with both local and systemic side effects. In this study, we describe a selective non-steroidal glucocorticoid receptor (GR) agonist for topical use, LEO 134310, which is rapidly deactivated in the blood resulting in low systemic exposure and a higher therapeutic index in the TPA-induced skin inflammation mouse model compared with betamethasone valerate (BMV) and clobetasol propionate (CP). Selectivity of LEO 134310 for GR was confirmed within a panel of nuclear receptors, including the mineralocorticoid receptor (MR), which has been associated with induction of skin atrophy. Topical treatment with LEO 134310 in minipigs did not result in any significant reduction in epidermal thickness in contrast to significant epidermal thinning induced by treatment with BMV and CP. Thus, the profile of LEO 134310 may potentially provide an effective and safer treatment option for skin diseases compared with currently used glucocorticoids.

682 Characterization of a novel selective non-steroidal glucocorticoid receptor agonist with low systemic exposure and reduced potential for skin atrophy

Topical glucocorticoids (GCs) are widely used drugs in dermatology but are associated with both local and systemic adverse effects. With the aim to provide an effective but safer topical treatment, we here describe LEO 134310, a novel non-steroidal glucocorticoid receptor (GR) agonist with low systemic exposure and reduced potential for induction of skin atrophy. LEO 134310 is a full GR agonist with high affinity for GR and nanomolar potency in human PBMCs. Furthermore, selectivity for GR was demonstrated within a panel of nuclear hormone receptors, including the mineralocorticoid receptor, which has been associated with induction of skin atrophy. Topical treatment with LEO 134310 in human skin explants resulted in full agonism, measured by GR target engagement, with maximal effects comparable to BMV and CP, although at higher dosage strength. The lower potency of LEO 134310 in human skin explants could be explained by a combination of lower skin penetration, metabolism in the skin and in vitro potency. LEO 134310 was rapidly deactivated in the blood and other compartments by enzymatic hydrolysis, leading to low systemic exposure of active parent compound. Consequently, a 10-fold higher therapeutic index was achieved with LEO 134310 compared to BMV and CP in the TPA-induced skin inflammation mouse model. Induction of skin atrophy after topical treatment with LEO 134310 in minipigs was minimal in contrast to significant epidermal thinning induced by treatment with CP and BMV. In conclusion, LEO 134310 may potentially offer an improved topical treatment solution for patients with inflammatory skin diseases.

430 Preclinical evaluation of a novel non-steroidal glucocorticoid receptor agonist with low systemic exposure and reduced potential for skin atrophy

Topical corticosteroids are widely used efficacious drugs but are associated with both local and systemic adverse effects. With the aim to provide an effective but safer topical treatment, we here describe a novel non-steroidal glucocorticoid receptor (GR) agonist with low systemic exposure and reduced potential for skin atrophy induction. LEO 134310 was shown to be a full GR agonist with high affinity for GR and low nanomolar potency in an inflammatory functional assay in human PBMCs. GR was the only nuclear hormone receptor affected by LEO 134310 in a panel of nuclear receptors, including the mineralocorticoid receptor, a receptor which has been associated with induction of skin atrophy. In blood and liver LEO 134310 is rapidly inactivated at a labile site, leading to high systemic clearance. In accordance with this profile, topical treatment with LEO 134310 in a TPA-induced dermatitis mouse model resulted in comparable efficacy to betamethasone valerate (BMV), with no systemic adverse effects at maximally effective doses. In contrast, BMV and clobetasol propionate (CP) markedly reduced body weight at maximally effective doses after topical treatment. Furthermore, skin atrophy after 4-week application to minipigs was minimal after treatment with LEO 134310 compared with significant skin atrophy induced by treatment with CP and BMV. LEO 134310 showed similar levels of target engagement as BMV, measured by FKBP5 mRNA, but lower than CP. Finally, topical treatment with LEO 134310 in a human skin explant model resulted in full agonism, measured by GR target engagement, albeit at higher dosage strength than required for BMV and CP. In conclusion, LEO 134310A shows an improved therapeutic index in preclinical studies compared to traditional corticosteroids and may potentially offer an improved topical treatment solution for patients with atopic dermatitis and psoriasis.

A nonsteroidal glucocorticoid receptor agonist inhibits allergen-induced late asthmatic responses.

Effective antiinflammatory therapies are needed for the treatment of asthma, but preferably without the systemic adverse effects of glucocorticosteroids. We evaluated the effect of an inhaled nonsteroidal glucocorticoid receptor agonist, AZD5423, on allergen-induced responses. Twenty subjects with mild allergic asthma were randomized to receive 7 days of treatment with nebulized AZD5423 (75 or 300 μg) once daily, budesonide 200 μg twice daily via Turbuhaler, or placebo in a double-blind, four-period, crossover design study. Allergen challenge was performed on Day 6. FEV1 was measured repeatedly for 7 hours after allergen challenge for early and late asthmatic responses. Sputum inflammatory cells was measured before and at 7 and 24 hours after allergen challenge, and methacholine airway responsiveness was measured before and 24 hours after allergen challenge. AZD5423 significantly attenuated the fall in FEV1 during the late asthmatic response (both doses led to an 8.7% fall) versus placebo (14% fall) (P < 0.05) with no effect of budesonide (12.5% fall) versus placebo (P > 0.05). There was no effect on the fall in FEV1 during early asthmatic response. AZD5423 300 and 75 μg significantly attenuated allergen-induced sputum eosinophilia by 63 and 61% at 7 hours, respectively, and by 46 and 34% at 24 hours after allergen challenge, respectively, versus placebo (all P < 0.05). Budesonide did not reduce allergen-induced sputum eosinophilia versus placebo. AZD5423 at 300 μg significantly attenuated allergen-induced airway hyperresponsiveness at 24 hours after allergen challenge versus placebo (P < 0.05). Both doses of AZD5423 were well tolerated. Seven-day treatment with inhalation of the nonsteroidal glucocorticoid receptor agonist AZD5423 effectively reduced allergen-induced responses in subjects with mild allergic asthma. Clinical trial registered with www.clinicaltrials.gov (NCT01225549).

Discovery of a potent and dissociated non-steroidal glucocorticoid receptor agonist containing an alkyl carbinol pharmacophore

Synthesis and structure–activity relationship (SAR) of a series of alkyl and cycloalkyl containing non-steroidal dissociated glucocorticoid receptor (GR) agonists is reported. This series of compounds was identified as part of an effort to replace the CF3 group in a scaffold represented by 1a. The study culminated in the identification of compound 14, a t-butyl containing derivative, which has shown potent activity for GR, selectivity against the progesterone receptor (PR) and the mineralocorticoid receptor (MR), in vitro anti-inflammatory activity in an IL-6 transrepression assay, and dissociation in a MMTV transactivation counter-screen. In a collagen-induced arthritis mouse model, 14 displayed prednisolone-like efficacy, and lower impact on body fat and free fatty acids than prednisolone at an equivalent anti-inflammatory dose.

Synthesis and structure–activity relationships of novel indazolyl glucocorticoid receptor partial agonists

SAR was used to further develop an indazole class of non-steroidal glucocorticoid receptor agonists aided by a GR LBD (ligand-binding domain)-agonist co-crystal structure described in the accompanying paper. Progress towards discovering a dissociated GR agonist guided by human in vitro assays biased the optimization of this compound series towards partial agonists that possessed excellent selectivity against other nuclear hormone receptors.

Boehringer Ingleheim's selective glucocorticoid receptor agonist development candidate: evaluation of WO2010141331, WO2010141332 and WO2010141333

Three applications from Boehringer Ingelheim all relate to the preparation of non-steroidal glucocorticoid receptor agonists useful in the treatment of inflammatory respiratory diseases. The first two applications claim chiral processes for the preparation of these compounds or intermediates useful therein. These provide two alternative routes, respectively, using achiral and chiral reagents. The third application relates to the preparation of a crystalline salt of the preferred compound on a multi-kilogram scale in micronised form.

Discovery of a potent series of non-steroidal non α-trifluoromethyl carbinol glucocorticoid receptor agonists with reduced lipophilicity

A novel series of indazole non-steroidal glucocorticoid receptor agonist has been discovered. This series features a sulfonamide central core and meta amides which interact with the extended ligand binding domain. This series has produced some of the most potent and least lipophilic agonists of which we are aware such as 20a (NFκB pIC(50) 8.3 (100%), clogP 1.9). Certain analogues in this series also display evidence for modulated pharmacology.

Tetrahydroquinoline glucocorticoid receptor agonists: Discovery of a 3-hydroxyl for improving receptor selectivity

We have previously disclosed a series of glucocorticoid receptor (GR) ligands derived from 6-indole-1,2,3,4-tetrahydroquinolines through structure–activity relationship (SAR) of the pendent C6-indole ring. In parallel with this effort, we now report SAR of the tetrahydroquinoline A-ring that identified the importance of a C3 hydroxyl in improving GR selectivity within a series of non-steroidal GR agonists.

Correlation of Skin Blanching and Percutaneous Absorption for Glucocorticoid Receptor Agonists by Matrix-Assisted Laser Desorption Ionization Mass Spectrometry Imaging and Liquid Extraction Surface Analysis with Nanoelectrospray Ionization Mass Spectrometry

Matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) and liquid extraction surface analysis (LESA) with nanoelectrospray ionization mass spectrometry (nESI-MS) have both been successfully employed to determine the degree of percutaneous absorption of three novel nonsteroid glucocorticoid receptor (GR) agonists in porcine ear sections. Historically, the ability of a glucocorticoid to elicit a skin blanching response when applied at low dose in ethanol solution to the forearms of healthy human volunteers has been a reliable predictor of their topical anti-inflammatory activity. While all three nonsteroidal GR agonists under investigation caused a skin blanching effect, the responses did not correlate with in vitro GR agonist potencies and different time courses were also observed for the skin blanching responses. MALDI MSI and LESA with nESI-MS were used to investigate and understand these different responses. The findings of the investigation was that the depth of porcine skin penetration correlates to the degree of skin blanching obtained for the same three compounds in human volunteers.

Structure Guided Design of 5-Arylindazole Glucocorticoid Receptor Agonists and Antagonists

Glucocorticoid receptor (GR) agonists have been used for more than half a century as the most effective treatment of acute and chronic inflammatory conditions despite serious side effects that accompany their extended use that include glucose intolerance, muscle wasting, skin thinning, and osteoporosis. As a starting point for the identification of GR ligands with an improved therapeutic index, we wished to discover selective nonsteroidal GR agonists and antagonists with simplified structure compared to known GR ligands to serve as starting points for the optimization of dissociated GR modulators. To do so, we selected multiple chemical series by structure guided docking studies and evaluated GR agonist activity. From these efforts we identified 5-arylindazole compounds that showed moderate binding to the glucocorticoid receptor (GR) with clear opportunities for further development. Structure guided optimization was used to design arrays that led to potent GR agonists and antagonists. Several in vitro and in vivo experiments were utilized to demonstrate that GR agonist 23a (GSK9027) had a profile similar to that of a classical steroidal GR agonist.

Identification of dissociated non-steroidal glucocorticoid receptor agonists

A new series of ligands for the glucocorticoid receptor (GR) is described. SAR development was guided by docking 3 into the GR active site and optimizing an unsubstituted phenyl ring for key interactions found in the steroid A-ring binding pocket. To identify compounds with an improved side effect profile over marketed steroids the functional activity of compounds was evaluated in cell based assays for transactivation (aromatase) and transrepression (IL-6). Through this effort, 36 has been identified as a partial agonist with a dissociated profile in these cell based assays.