Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Crf1 receptor antagonists for the treatment of congenital adrenal hyperplasia

a technology of congenital adrenal hyperplasia and receptor antagonists, which is applied in the direction of endocrine system disorders, drug compositions, medical preparations, etc., can solve problems such as disease severity, and achieve the effects of reducing high plasma acth levels, potent ability to lower acth, and inhibiting specific binding

Inactive Publication Date: 2017-01-26
NEUROCRINE BIOSCI INC
View PDF1 Cites 18 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent discusses a treatment for patients with congenital adrenal hyperplasia (CAH) using corticotropin-releasing factor (CRF) antagonists. These antagonists can inhibit the release of adrenal cortex hormones, leading to a reduction in the amount of hydrocortisone needed for treatment. This can lead to better outcomes with lower doses of the medication and fewer side effects.

Problems solved by technology

These mutations can range from complete loss of enzyme activity required for synthesis of cortisol in the adrenal cortex to a spectrum of partial loss, which results in disease severity that is a direct consequence of a specific mutation.
These patients require lifelong management with glucocorticoids and the attendant problems associated with such treatment.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Crf1 receptor antagonists for the treatment of congenital adrenal hyperplasia
  • Crf1 receptor antagonists for the treatment of congenital adrenal hyperplasia
  • Crf1 receptor antagonists for the treatment of congenital adrenal hyperplasia

Examples

Experimental program
Comparison scheme
Effect test

example 1

CRF Receptor Binding Activity

[0075]CRF antagonists as used in the methods described herein may be evaluated for binding activity to the CRF receptor by a standard radioligand binding assay as generally described by Grigoriadis et al. (see, e.g., Mol. Pharmacol vol 50, pp 679-686, 1996) and Hoare et al. (see, e.g., Mol. Pharmacol 63: 751-765, 2003.) By utilizing radiolabeled CRF ligands, the assay may be used to evaluate the binding activity of the compounds described herein with any CRF receptor subtype.

[0076]Briefly, the binding assay involves the displacement of a radiolabeled CRF ligand from the CRF receptor. More specifically, the binding assay is performed in 96-well assay plates using 1-10 μg cell membranes from cells stably transfected with human CRF receptors. Each well receives about 0.05 mL assay buffer (e.g., Dulbecco's phosphate buffered saline, 10 mM magnesium chloride, 2 mM EGTA) containing compound of interest or a reference ligand (for example, sauvagine, urocortin I...

example 2

CRF1 Receptor Agonist Activity

[0077]As reported in Fleck et al. (J. Pharmacology and Experimental Therapeutics, 341(2):518-531, 2012) (hereinafter “Fleck et al.” and incorporated by reference in it's entirely) the activity of previously identified CRF1 receptor antagonists are presented. Such activity is reported as the kinetically derived affinity (Ki) calculated from the association (k1) and dissociation (k−1) rate constants by the following equation:

Ki=k−1 / ki

[0078]Also as reported in Fleck et al., the kinetic Ki of the CRF1 receptor antagonists listed in Table 1 below have been reported:

TABLE 1Representative CRF1 Receptor Antagonistsk1Kinetic KiLigand(106 M−1min−1)(nM)NBI-279149.4 ± 3  25CP-316,31113 ± 2 12NBI-462006.2 ± 2  22DMP6967.7 ± 2  9.5pexacerfont2.6 ± 0.119NBI-3596520 ± 2 2.3ONO-2333Ms4.4 ± 2.215antalarmin3.4 ± 0.63.9NBI-340418.3 ± 2.01.7DMP90418 ± 1 0.38NBI-30775 14 ± 2.00.36SSR125543A33 ± 5 0.049NBI-778600.24 ± 0.0548 ± 9

[0079]By this same technique, the kinetic Ki of...

example 3

Dissociation Half-Life (T1 / 2) of CRF1 Receptor Antagonists

[0080]The dissociation half-life (t1 / 2) of a CRF1 receptor antagonist as used in the methods described herein is evaluated by the technique described in Fleck et al. As described therein, the dissociation rate constant for labeled and unlabeled ligands is denoted as k−1, while the half-life of drug dissociation from the receptor (t1 / 2), which is equal to the median residence time, is calculated from the dissociation rate constant (k−1) by the following equation:

t1 / 2=0.693 / k−1

[0081]As reported in Fleck et al., the dissociation half-life (t1 / 2) of the CRF1 receptor antagonists listed in Table 2 below have been reported.

TABLE 2Dissociation Half-Life of Representative Compoundsk−1,Dissociation t1 / 2,Ligand(min−1)(min)NBI 279140.27 ± 0.072.6CP-316,3110.17 ± 0.044.1NBI-46200 0.13 ± 0.0025.3DMP6960.095 ± 0.02 7.3pexacerfont0.049 ± 0.00114NBI-359650.048 ± 0.00516ONO-2333Ms0.063 ± 0.02917antalarmin0.013 ± 0.00253NBI-340410.013 ± 0.002...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

PropertyMeasurementUnit
dissociation half-lifeaaaaaaaaaa
Compositionsaaaaaaaaaa
enzyme activityaaaaaaaaaa
Login to View More

Abstract

CRF1 receptor antagonists have the potential to directly inhibit ACTH release in patients with CAH and thereby allow normalization of androgen production while using lower, more physiologic doses of hydrocortisone, and thus reducing treatment-associated side effects.

Description

BACKGROUND[0001]Technical Field[0002]Compositions and methods for treating congenital adrenal hyperplasia are described herein.[0003]Description of the Related Art[0004]Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive genetic disorders that result in little or no cortisol biosynthesis. The most frequent form of the disease is 21-hydroxylase deficiency caused by mutations in the CYP21A2 gene located on chromosome 6p21, which accounts for approximately 95% of CAH cases (see, e.g., Speiser et al., Int. J. Pediatr. Endocrinol. 2010:494173 (2010) for a review). These mutations can range from complete loss of enzyme activity required for synthesis of cortisol in the adrenal cortex to a spectrum of partial loss, which results in disease severity that is a direct consequence of a specific mutation. This continuum of 21-hydroxylase deficiency has been broadly classified into salt-wasting and simple-virilizing forms, grouped as classical CAH, and the milder form known as...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/519
CPCA61K31/519A61K31/427A61K31/4985A61P5/38A61K31/4245
Inventor GRIGORIADIS, DIMITRI E.
Owner NEUROCRINE BIOSCI INC
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com