Use of uridine 5'-diphosphate and analogs thereof for the treatment of lung diseases

A technology of compounds and medicinal salts, applied in the direction of respiratory diseases, medical preparations containing active ingredients, drug combinations, etc., can solve problems such as not realizing that it is useful for treating tracheal diseases

Inactive Publication Date: 2000-09-27
THE UNIV OF NORTH CAROLINA AT CHAPEL HILL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Despite the fact that about P2Y 6 Evidence for the receptor and its relationship to UDP, which has so far not been recognized to be useful in the treatment of airway disease

Method used

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  • Use of uridine 5'-diphosphate and analogs thereof for the treatment of lung diseases
  • Use of uridine 5'-diphosphate and analogs thereof for the treatment of lung diseases
  • Use of uridine 5'-diphosphate and analogs thereof for the treatment of lung diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Method: Cell Culture

[0060] Human nasal epidermal cells were harvested from turbinates using protease XIV (Sigma, St.Louis, MO) at 4°C for 24-48 hours as previously described, R.Wu, et al., American Review of Respiratory Diseases (Am.Rev Respir. Dis.) 132, 311-320 (1985). Cytosolic calcium ions and inositol phosphate assays were performed on porous Transwell Col filters (pore diameter 0.45 μm; Costar, Cambridge, MA) maintained in Ham's F12 medium supplemented with 10 ng / mL epidermal growth factor, 3.75ng / mL epidermal growth factor, 500ng / mL hydrocortisone, 5ng / ml insulin, and 1mM CaCl 2 (Ham's F12+4X matrix). The assay is performed on days 7-10 after inoculation, which is the time coincident with the development of the maximum transepidermal potential difference according to N. Nakahata and T. K. Harden, Biochem. J. 241, 337-344 (1987).

Embodiment 2

[0062] Method: Determination of inositol phosphate

[0063] The fusion human nasal epithelial cells described in Example 1 were mixed with 4.5 g / L glucose and 5 μCi / mL[ 3 H] Inositol labeling in inositol-free DMEM for 18 hr. The cells were pre-incubated with 10 mM lithium chloride and challenged with agonist for 10 minutes. To prepare the same matrix, add [ 3 H] myo-inositol to avoid the release of endogenous ATP by stressed cells. E.R. Lazarowski et al., Br. J. Pharmacol 116, 1619-1627 (1995). Add 5% ice-cold trichloroacetic acid to stop the incubation, and separate the obtained [ 3 H] Inositol phosphate, according to the method described by A.M. Paradiso et al., Nature (Nature) 377, 643-646 (1995).

Embodiment 3

[0065] Methods: Bioelectricity and Cytosolic Ca 2+ Joint determination of

[0066] Nasal cells grown on Transwell Col filters with O-rings maintained in F12+4X matrix were studied 7-10 days after plating cells as described above. for Ca 2+ i Assay, load cells with Fura-2, then place the cells in a micro-Ussing chamber on a microscope (Zeiss) objective lens connected to a microfluorometer, and measure cytosolic Ca according to the method described in Paradiso et al., above. 2+ i content. Collect the fluorescence intensity ratio (excitation wavelength 340 / 380; emission wavelength λ450nm) from the area of ​​30-40 nasal cells on the monolayer surface, and then convert according to the method of E.H.Larsen et al., J.Physiol (J.Physiol) 424, 109-131 (1990) into Ca 2+ concentration. For the simultaneous determination of Cl - For the secretion, the transepithelial potential difference (TEP) was measured by Voltage-Clamp / Pulse Generator (Model VCC600, Physiological In...

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Abstract

Compounds of Formula I: wherein: X1, and X2 are each independently either O- or S-; X3 and X4 are each independently either -H or -OH, with the proviso that X3 and X4 are not simultaneously -H; R1 is selected from the group consisting of O, imido, methylene and dihalomethylene; R2 is selected from the group consisting of H, halo, alkyl, substituted alkyl, alkoxyl, nitro and azido; R3 is selected from the group consisting of H, alkyl, acyl, aryl, and arylalkyl; and R4 is selected from the group consisting of -OR', -SR', -NR', and -NR'R'', wherein R' and R'' are independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, alkoxyl, and aryloxyl, with the proviso that R' is absent when R4 is double bonded from an oxygen or sulfur atom to the carbon at the 4-position of the pyrimidine ring, are used in methods of hydrating lung mucus secretions and treating lung disorders such as cystic fibrosis, ventilator-associated pneumonia, chronic bronchitis, chronic obstructive pulmonary disorder and primary ciliary dyskinesia. Pharmaceutical compositions containing compounds of Formula I, and novel compounds of Formula I are also described.

Description

[0001] related application [0002] This application claims the benefit of US Provisional Application No. 60 / 057,064, filed August 29, 1997, which is hereby incorporated by reference in its entirety. [0003] government support [0004] This invention was made with US Government support under Grant #2PO1 HL32322-11A1 from the National Institutes of Health. The United States government has patent rights in this invention. field of invention [0005] The present invention relates to methods for the treatment of pulmonary diseases, novel compounds and pharmaceutical compositions for use in such treatment. Background of the invention [0006] In cystic fibrosis and other lung diseases in which the water content of lung mucus is altered, a therapeutic goal is to hydrate lung mucus secretions, which may be more easily cleared by mucociliary action or coughing alone subsequent secretions. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/00A61K31/7042A61K31/7052A61K31/7064A61K31/7068A61K31/7072A61K45/06A61P11/00C07H19/10
CPCC07H19/10A61K31/7068A61K31/7072Y10S514/826A61K9/0073Y10S514/851A61K45/06A61P11/00A61P11/12A61K2300/00A61K31/70
Inventor R·C·小道切尔S·R·沙沃W·潘德加斯特B·耶尔克萨J·L·瑞狄奥特R·道格赫提D·克罗姆
Owner THE UNIV OF NORTH CAROLINA AT CHAPEL HILL
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