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Short-acting selective glucocorticoid receptor modulators

A technology for acute stress and hypercortisolism, applied in the direction of sugar-coated pills, pill delivery, organic active ingredients, etc., can solve problems such as delaying sleep onset and disrupting sleep maintenance

Pending Publication Date: 2021-11-12
熊猫咨询有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Excessive arousal from a stressful day can severely delay sleep onset and disrupt sleep maintenance

Method used

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  • Short-acting selective glucocorticoid receptor modulators
  • Short-acting selective glucocorticoid receptor modulators
  • Short-acting selective glucocorticoid receptor modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0085] Metabolic Stability and Blood Brain Barrier Passability of Formula I, Formula II, Formula III, Formula IV, and Formula V

[0086] The metabolic stability of each compound of Formulas I-V is unknown or known to be very short (e.g., in vitro data for Formula I, reported half-lives of 0.33 hours in rat liver microsomes and less than 0.2 hours in rat hepatocytes; Formula IV is reported to be converted to an unidentified metabolite within 30 minutes in rat liver microsomes). This led to the discontinuation of previous development of such short-acting GR ligands in favor of more metabolically stable compounds.

[0087] The metabolic stability of each compound of Formula I, Formula II, Formula III, Formula IV, and Formula V can be investigated. The compound should have limited metabolic stability in vitro and in vivo compared to mifepristone (RU-486, a progesterone receptor modulator that also exhibits anti-glucocorticoid properties).

[0088] To determine metabolic stabilit...

Embodiment 2

[0092] Short-acting selective glucocorticoid receptor modulators in a mouse model of stress-induced anxiety

[0093] Formula I, Formula II, Formula III, Formula IV, and Formula V constitute chemically diverse SASGRMs with similar biological properties. They show selectivity for glucocorticoid receptor (GR) binding, selective GR antagonism in vitro, limited metabolic stability in vitro and in vivo, as indicators of HPA axis disinhibition in mice after oral administration In vivo corticosterone levels did not increase after the drug, with low plasma protein binding and moderate to high BBB permeation potential.

[0094] In a mouse model of stress-induced anxiety, Formula III (also known as PND-001) as a representative compound in the SASGRM class was tested by the elevated plus maze test (EPM) (Experiment 1). EPM avoids the aversive properties of bright open arms by relying on an inherent conflict between the rodent's propensity to explore new environments on the one hand and t...

Embodiment 3

[0135] Preparation of coated pellets for immediate release (of micronized RU 43044 (formula I))

[0136] The particle size of RU 43044 (Formula I) can be significantly reduced, for example, by using specific milling techniques such as jet milling in a steel chamber under nitrogen pressure. When RU 43044 (Formula I) powder is fed into the grinding chamber at a velocity of about 50 m / s and the faster particles accelerated to a velocity of about 300 m / s by a series of jet nozzles collide with the slower particles of the input , micronization occurs. Using laser diffraction measurements, the particle size distribution (by volume) of RU 43044 that can be achieved by the jet milling technique described above is about 2-3 μm (d50), 10-12 μm (d99) and <15 μm (d100).

[0137] A preferred dosage form is a multiparticulate system consisting of multiparticulates of 1-3 mm in size, which ensures rapid gastric emptying, low variability in gastric transit time and optimized absorption of th...

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PUM

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Abstract

The invention provides short-acting selective glucocorticoid receptor modulators for preventing, relieving or treating symptoms, disorders and diseases associated with acute stress or temporary hypercortisolism and compositions comprising immediate release and a plurality of delayed pulse releases of the modulators.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims the benefit of US Provisional Patent Application No. 62 / 785,761, filed on December 28, 2018, which is incorporated herein by reference in its entirety. technical field [0003] The present invention generally relates to the field of prevention, mitigation and treatment of symptoms, disorders and diseases associated with acute stress or transient hypercortisolism. More specifically, the present invention relates to hydroxy-androst-4,9(11)-dien-3-one (eg, RU-43044), 21-hydroxy-6,19-oxyprogesterone, by administration Ketones, 16-hydroxy-11-(substituted phenyl)-estra-4,9-diene (eg ORG 36410), 17-beta-carboxamide of dexamethasone and Δ1-11-oxa-11- Immediate release, delayed release and / or pulsatile release compositions of short-acting selective glucocorticoid receptor modulators ("SASGRMs") of deoxycortisol to prevent, alleviate and treat stress-related academic and educational problems, Symptoms of a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/567A61K31/575A61P25/00
CPCA61K31/575A61P25/00A61K31/569A61K31/57A61K9/2846A61K9/2886A61P25/22A61K9/0004A61K9/4866A61K9/5026A61K31/352A61K31/56A61K31/567A61K31/573A61K31/58
Inventor 鲁斯·蒂尔洛夫-埃克尔特
Owner 熊猫咨询有限责任公司
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