1H-Pyrazolo[3,4-g]hexahydro-isoquinolines as selective glucocorticoid receptor antagonists with high functional activity

Clark, Robin D.; Ray, Nicholas C.; Williams, Karen; Blaney, Paul; Ward, Stuart D.C.; Crackett, Peter H.; Hurley, Christopher A.; Dyke, Hazel J.; Clark, David E.; Lockey, Peter; Devos, René; Wong, Melanie; Porres, Soraya S.; Bright, Colin P.; Jenkins, Robert E.; Belanoff, Joseph K.

doi:10.1016/j.bmcl.2008.01.027

Cited by 48 publications

(31 citation statements)

References 16 publications

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“…C108297 is expected to have selective modulator effects also in peripheral tissues that we did not examine here (34). We did not determine binding to MRs and PRs or specific MR/PR readouts here, but previous studies showed 0% displacement from MR and 26% from PR at 10 μM C108297, i.e., over a 1000-fold selectivity for GR (18). In peripheral tissues, we cannot exclude some binding to PR with the 20 mg/kg dose C108297, but under nonsaturating conditions for brain GR, activation of other steroid receptors is unlikely.…”

Section: Discussionmentioning

confidence: 98%

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Differential targeting of brain stress circuits with a selective glucocorticoid receptor modulator

Zalachoras

Houtman²,

Atucha

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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103

137

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Glucocorticoid receptor (GR) antagonism may be of considerable therapeutic value in stress-related psychopathology such as depression. However, blockade of all GR-dependent processes in the brain will lead to unnecessary and even counteractive effects, such as elevated endogenous cortisol levels. Selective GR modulators are ligands that can act both as agonist and as antagonist and may be used to separate beneficial from harmful treatment effects. We have discovered that the high-affinity GR ligand C108297 is a selective modulator in the rat brain. We first demonstrate that C108297 induces a unique interaction profile between GR and its downstream effector molecules, the nuclear receptor coregulators, compared with the full agonist dexamethasone and the antagonist RU486 (mifepristone). C108297 displays partial agonistic activity for the suppression of hypothalamic corticotropin-releasing hormone (CRH) gene expression and potently enhances GR-dependent memory consolidation of training on an inhibitory avoidance task. In contrast, it lacks agonistic effects on the expression of CRH in the central amygdala and antagonizes GR-mediated reduction in hippocampal neurogenesis after chronic corticosterone exposure. Importantly, the compound does not lead to disinhibition of the hypothalamus-pituitary-adrenal axis. Thus, C108297 represents a class of ligands that has the potential to more selectively abrogate pathogenic GR-dependent processes in the brain, while retaining beneficial aspects of GR signaling.HPA axis | neuroendocrinology | steroid pharmacology | transcription regulation | NCoA1

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Section: Discussionmentioning

confidence: 98%

“…C108297 [or compound 47 from ref. 18] has a K i of 0.9 nM for GR and >10 μM for progesterone receptor (PR), MR, and androgen receptor (18). It shows GR antagonism in relation to GRdependent CRH mRNA regulation in the amygdala and corticosterone-induced reduction in hippocampal neurogenesis.…”

mentioning

confidence: 99%

Differential targeting of brain stress circuits with a selective glucocorticoid receptor modulator

Zalachoras

Houtman²,

Atucha

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

103

137

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“…SGRMs without AR or PR cross-reactivity) is an important step toward implementing GR antagonism as a targeted therapy in CRPC. SGRMs CORT118335 and CORT108297 (Table 1) are two non-steroidal highly specific GR ligands that have been developed based on potent functional GR antagonism without significant binding to other members of the nuclear hormone receptor family (28,29). …”

Section: Introductionmentioning

confidence: 99%

Selective Glucocorticoid Receptor Modulators (SGRMs) Delay Castrate-Resistant Prostate Cancer Growth

Kach

Long

Selman

et al. 2017

Molecular Cancer Therapeutics

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Increased glucocorticoid receptor (GR) expression and activity following androgen blockade can contribute to castration-resistant prostate cancer (CRPC) progression. Therefore, we hypothesized that GR antagonism will have therapeutic benefit in CRPC. However, the FDA-approved nonselective, steroidal GR antagonist, mifepristone, lacks GR specificity, reducing its therapeutic potential. Here we report that two novel non-steroidal and highly selective GR modulators (SGRMs), CORT118335 and CORT108297, have the ability to block GR activity in prostate cancer (PC) and slow CRPC progression. In contrast to mifepristone, these novel SGRMs did not affect AR signaling, but potently inhibited GR transcriptional activity. Importantly, SGRMs decreased GR-mediated tumor cell viability following AR blockade. In vivo, SGRMs significantly inhibited CRPC progression in high GR-expressing, but not in low GR-expressing xenograft models. Transcriptome analysis following AR blockade and GR activation revealed that these SGRMs block GR-mediated proliferative gene expression pathways. Furthermore, GR-regulated proliferation-associated genes AKAP12, FKBP5, SGK1, CEBPD, and ZBTB16 are inhibited by CORT108297 treatment in vivo. Together, these data suggest that GR-selective non-steroidal SGRMs potently inhibit GR activity and PC growth despite AR pathway inhibition demonstrating the therapeutic potential of SGRMs in GR-expressing CRPC.

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“…CORT 108297 is a selective glucocorticoid receptor antagonist and has a GR binding and functional profile similar to mifepristone with sub-nanomolar affinity for human GR and less than 10 nM GR functional activity in a luciferase-based reporter gene assay. Unlike mifepristone, it has no activity at the progesterone (PR) receptor [20]. An additional control group ( n = 8) was fed a standard chow diet and tap water and did not receive any treatment.…”

Section: Methodsmentioning

confidence: 99%

Selective Glucocorticoid Receptor (GR-II) Antagonist Reduces Body Weight Gain in Mice

Asagami

Belanoff

Azuma

et al. 2011

Journal of Nutrition and Metabolism

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Previous research has shown that mifepristone can prevent and reverse weight gain in animals and human subjects taking antipsychotic medications. This proof-of-concept study tested whether a more potent and selective glucocorticoid receptor antagonist could block dietary-induced weight gain and increase insulin sensitivity in mice. Ten-week-old, male, C57BL/6J mice were fed a diet containing 60% fat calories and water supplemented with 11% sucrose for 4 weeks. Groups (n = 8) received one of the following: CORT 108297 (80 mg/kg QD), CORT 108297 (40 mg/kg BID), mifepristone (30 mg/kg BID), rosiglitazone (10 mg/kg QD), or vehicle. Compared to mice receiving a high-fat, high-sugar diet plus vehicle, mice receiving a high-fat, high-sugar diet plus either mifepristone or CORT 108297 gained significantly less weight. At the end of the four week treatment period, mice receiving CORT 108297 40 mg/kg BID or CORT 108297 80 mg/kg QD also had significantly lower steady plasma glucose than mice receiving vehicle. However, steady state plasma glucose after treatment was not highly correlated with reduced weight gain, suggesting that the effect of the glucocorticoid receptor antagonist on insulin sensitivity may be independent of its mitigating effect on weight gain.

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1H-Pyrazolo[3,4-g]hexahydro-isoquinolines as selective glucocorticoid receptor antagonists with high functional activity

Cited by 48 publications

References 16 publications

Differential targeting of brain stress circuits with a selective glucocorticoid receptor modulator

Differential targeting of brain stress circuits with a selective glucocorticoid receptor modulator

Selective Glucocorticoid Receptor Modulators (SGRMs) Delay Castrate-Resistant Prostate Cancer Growth

Selective Glucocorticoid Receptor (GR-II) Antagonist Reduces Body Weight Gain in Mice

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