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P2Y6 receptor agonists for treating lung diseases

A lung, disease technology, applied in the field of P2Y6 receptor agonist compounds, can solve problems such as lack of understanding and low potency

Inactive Publication Date: 2008-08-06
INSPIRE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

P2Y 6 The receptor's natural agonist UDP promotes mucociliary clearance less potently than P2Y 2 Agonists, natural P2Y not yet known 6 Whether the low potency of the receptor agonist UDP is due to its susceptibility to metabolic liability

Method used

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  • P2Y6 receptor agonists for treating lung diseases
  • P2Y6 receptor agonists for treating lung diseases
  • P2Y6 receptor agonists for treating lung diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0128] Example 1. Preparation of P 1 -(2',3'-Benzyluridine 5'-)P 3 -(Uridine 5'-)ammonium triphosphate

[0129] Uridine 5'-tributylammonium diphosphate (UDP.NBu 3 )

[0130] Dowex 50 H with uridine 5'-diphosphate disodium (UDP.2Na) and water + Or equivalent (5g resin / gUDP.2Na) was stirred for 10 minutes to convert it to the free acid. The resin was filtered and the filtrate was mixed with tributylamine (1.5 equiv). The mixture was stirred vigorously for 15 minutes to keep the pH of the aqueous layer above 8. The solution was evaporated below 35°C and the residue was co-evaporated with anhydrous N,N-dimethylformamide (3X) below 40°C. The residue was lyophilized overnight to give a dry glassy foam.

[0131] Uridine 5'-tributylammonium monophosphate (UMP.NBu 3 )

[0132] The free acid form of uridine 5'-monophosphate (UMP) was converted to the mono-tributylammonium salt by treatment with aqueous tributylamine (1.5 equivalents). After removal of the solvent and co-evapora...

Embodiment 2

[0138] Embodiment 2. UDP, UP 3 U and monobenzyl acetal UP 3 U's selectivity

[0139] In 96-well plates will express P2Y 1 、P2Y 2 、P2Y 4 and P2Y 6 Human astrocytoma (1321N1) cells were cultured to confluence. Add the Fluo-3AM (2.5 μM final concentration) solution prepared with assay buffer consisting of 10 mM KCl, 118 mM NaCl, 2.5 mM CaCl 2 , 1mM MgCl 2 , 20mM HEPES, 10mM glucose, pH7.4 composition. After incubating with Fluo-3 AM at 25°C for 60 minutes, the cells were washed and treated with serially diluted concentrations of the compounds uridine 5'-diphosphate (UDP), P 1 , P 3 -(Diuridine 5'-)triphosphate (UP 3 U) or P 1 -(2',3'-Benzyluridine 5'-)P 3 -(Uridine 5'-)triphosphate (monobenzyl acetal UP 3 U) stimulation. Changes in fluorescence density were measured using FLIPR (Molecular Devices Corp., Sunnyvale, CA) while intracellular calcium levels were monitored in each well. The results of this experiment are shown in Table 1. Compound UDP, UP in Table 1 3 ...

Embodiment 3

[0144] Example 3. Chloride secretion by human nasal airway cells.

[0145] Induction of chlorine secretion in vivo can help to hydrate thick airway mucus secretions in patients with disease, allowing patients to benefit from the mobilization and clearance of these secretions. Activation of apical non-CFTR chloride channels induces chloride ion and water outflow, thereby aiding rehydration of pulmonary secretions (Boucher, US Patent 5,292,498 and Boucher, US Patent 5,635,160, and references cited therein).

[0146] Airway epithelial cells were dispersed and isolated from freshly excised human nasal surgical specimens (Yankaskas et al., Am Rev Resp Dis 132, 1281-1287 (1985)). Confluent monolayers of cells were grown on permeable collagen matrix supports in F-12 hormone-supplemented medium (Wu, et al., Am Rev Resp Dis 132, 311-320 (1985)). Cells were incubated at 37°C and grown to confluence. The occurrence of transepithelial electrical resistance was monitored to determine the...

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Abstract

The present invention relates to a method of increasing or facilitating the clearance of pulmonary mucus secretions in a subject. The present invention also relates to a method of facilitating hydration of pulmonary mucus secretions in a subject. The invention also relates to a method of preventing or treating a disease or condition associated with impaired lung or airway function in a human or other mammal. The method comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a P2Y6 receptor agonist compound, wherein said amount is effective to activate P2Y6 receptors on the luminal surface of the lung epithelium. The P2Y6 receptor agonist compounds used in the present invention include mononucleoside 5'-diphosphate, dinucleoside monophosphate, dinucleoside diphosphate or dinucleoside triphosphate of general formula I, or salts and solvates thereof , Hydrate.

Description

technical field [0001] The present invention relates to P2Y 6 Receptor agonist compounds and use of such compounds for the treatment of diseases or conditions associated with impaired lung and airway function in humans or other mammals. Background of the invention [0002] P2 receptor subtype P2Y 2 、P2Y 4 、P2Y 6 and adenosine receptor subtype A 2B Are expressed in the human airway. Instillation of ATP, UTP, or UDP into the lung improves mucociliary clearance of the airway epithelium. This response to extracellular nucleotides is triggered by activation of one or more P2Y receptors, leading to increased fluid and chloride secretion (P2Y 2 、P2Y 4 and P2Y 6 ), sodium absorption is inhibited (P2Y 2 、P2Y 4 and P2Y 6 ) and increased mucin secretion (P2Y 2 and P2Y 4 ). These events, in concert with increased ciliary beating frequency, are responsible for the natural clearance of the airways. See Kellerman, Chest. 121:201 S-205S (2002); Knowles, J Clin Invest. 109:571...

Claims

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Application Information

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IPC IPC(8): A01N43/04A61K31/70
Inventor J·L·博耶S·R·谢弗J·G·道格拉斯三世C·C·瑞迪克
Owner INSPIRE PHARMA
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