Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-21
2001-06-26
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S851000
Reexamination Certificate
active
06251930
ABSTRACT:
DESCRIPTION
1. Technical Field
The present invention is concerned with activating Cl
−
secretion in a patient. More particularly the present invention is especially concerned with treating patients suffering from cystic fibrosis by administering certain heterocyclic nitrogen containing compounds.
2. Background of Invention
Insufficient Cl
−
transport in epithelial cells has been associated with disease in individuals and especially with cystic fibrosis. In particular, the cystic fibrosis transmembrane conductance regulator (CFTR) functions as a Cl
−
channel. At the surface of epithelial cells, it also regulates the activity of other ion channels, including amiloride-sensitive Na
+
channels, and other Cl
−
transport pathways. Cystic fibrosis mice lack Cl
−
transport capabilities in their nasal airways, lung cells, and intestines. In human with cystic fibrosis, sweat ducts cannot properly reabsorb Cl
−
. It has also been suggested that the Pseudomonas predisposition in cystic fibrosis patients may be associated with defects in Cl
−
reabsorption, rather than secretion. These results collectively point to defects in Cl
−
transport as responsible for pathogenesis in the disease.
CFTR regulates airway Na
+
re-absorption through effects on epithelial sodium channels (ENaCs). CFTR may also regulate K
+
channels. Several studies have indicated important effects of wild-type CFTR on membrane turnover in epithelia, including regulation of both endo- and exocytosis. Acidification of intracellular compartments such as the golgi and proper in protein glycosylation and sialation have also been suggested to rely on normal CFTR function. Although CFTR may subserve other functions in epithelia, defective Cl
−
secretion into the airways is the best understood and most likely physiologic contributor to clinical disease. Nasal and lower airway potential difference measurements include abnormal Cl
−
secretion into CF airways. Correction of Cl
−
secretory defects are viewed as important and possibly the benchmark by which to evaluate the effectiveness of therapeutic interventions such as gene-based or other pharmacologic therapies. Cystic fibrosis mice are believed to be protected from lung disease because of alternate Cl
−
secretory pathways that are not found in the intestinal tracts of these animals, accounting for the absence of lung disease in the animal model. The absence of alternate Cl
−
secretory pathways in murine intestines of mice may explain the predisposition of CF mice towards lethal gastrointestinal pathophysiology. Finally, genetic modifiers than lessen the severity of disease in CF mice appear to activate alternate Cl
−
secretory pathways in the intestines of these animals. Because of a preponderance of evidence that Cl
−
secretion is not only associated with CF, but directly responsible for the disease, Cl
−
secretagogues form an important aspect of new pharmacologic approaches to treatment.
Scientific efforts directed towards identifying activators of Cl
−
secretion in CF tissues are an important aspect of drug discovery in the disease. Important evidence indicates that drugs in the sulfonylurea class can maintain certain K
+
channels in a tonically open-state. Channel openers that might have comparable action on CFTR or other Cl
−
transport pathways are being actively sought as part of therapeutic development in the disease. In principal, such agents might either activate residual CFTR activity at the cell surface, open alternate Cl
−
secretory pathways, or increase the gradient for apical Cl
−
secretion from cells, for example by opening basolateral K
+
channels and augmenting the tendency for Cl
−
to exit at the apical surface.
Nucleotides such as uridine triphosphate (UTP) and adenosine triphosphate (ATP) have been shown to activate Cl
−
secretion in CF tissues, including transepithelial transport in vivo. These drugs also transiently correct CF bioelectric abnormalities, and cause strong Cl
−
secretion as judged by in vivo measurements of airway potential difference. However, drugs such as UTP are rapidly cleared at the airway cell surface by endogenous ectonucleotidases, and therefore may have limited bioavailability in vivo. Moreover, the activities of compounds such as UTP are often short lived, and disappear within minutes unless fresh compound is continuously provided on to airway epithelium in vivo. Tachyphylaxis to UTP has been observed both in vitro and in vivo.
The drug CPX, a cyclopropyl xanthene, appears to directly activate &Dgr;F508 CFTR. CPX exhibits this activity in human CF pancreatic cells (CFPAC—cell line), in airway cells derived from a CF patient (IB3-1—cell line), and in NIH 3T3 cells after expression of the &Dgr;F508 protein. In all cases, Cl
−
efflux from these cells could be activated by CPX. Because CPX is believed to bind and activate &Dgr;F508 CFTR at the cell surface, the drug may only be active if sufficient &Dgr;F508 CFTR is present in the plasma membrane to permit induction of Cl
−
transport. Previous studies have suggested that levels of &Dgr;F508 CFTR present at the cell surface could be extremely low in vivo due to recognition of the &Dgr;F508 mutation by protein processing mechanisms in the endoplasmic reticulum that rapidly degrade the &Dgr;F508 protein.
In general, Cl
−
secretagogues act by elevating intra-cellular levels of either Ca
2+
or cyclic AMP (cAMP). For example, agents such as UTP, ATP, NS004, and duramycin are believed to activate secretion in CF tissues by elevating cellular Ca
2+
. Drugs such as adenosine and milrinone activate residual CFTR activity by signaling through cAMP and PKA.
SUMMARY OF INVENTION
The present invention is concerned with drugs that exhibit high activity and long-lived activity for activating Cl
−
secretion from CF airway and pancreatic cells and across cystic fibrosis tissues and cell monolayers.
Compounds employed according to the present invention provide relatively stable activation of Cl
−
secretion in CF cells and tissues and appear to work by a mechanism independent of either intracellular Ca
2+
or cAMP. Compounds employed according to the present invention elicit Cl
−
secretion that is active in CF and normal epithelia, and do not appear to require &Dgr;F508 CFTR at the cell surface.
The present invention is concerned with promoting or activating Cl
−
secretion in a patient in need thereof by administering to the patient a composition comprising a pharmaceutically acceptable carrier and an amount effective for promoting or activating Cl
−
secretion of a compound represented by the formula:
wherein A is a 5 or 6 membered unsaturated heterocyclic ring containing at least one N atom;
X
2
is O, NH, NR,
each R individually is alkyl, cycloalkyl, aryl, alkaryl and aralkyl,
each R
2
individually is H, alkyl, cycloalkyl, aryl, alkaryl and aralkyl;
Y is halogen; alkylthio group or nitrogenous moiety.
The present invention is also concerned with treating a patient suffering from cystic fibrosis by administering to the patient a composition comprising a pharmaceutically acceptable carrier and an amount effective for treating cystic fibrosis of a compound represented by the formula:
wherein A is a 5 or 6 membered unsaturated heterocyclic ring containing at least one N atom;
X
2
is O, NH, NR,
each R individually is alkyl, cycloalkyl, aryl, alkaryl and aralkyl,
each R
2
individually is H, alkyl, cycloalkyl, aryl, alkaryl and aralkyl;
Y is halogen; alkylthio group or nitrogenous moiety.
Still other objects and advantages of the present invention will become readily apparent by those skilled in the art from the following detailed description, wherein it is shown and described only the preferred embodiments of the invention, simply by way of illustration of the best mode contemplated of carrying out the invention. As will be realized the inventio
Maddry Joseph A.
Sorscher Eric J.
Connolly Bove Lodge & Hutz
Southern Research Institute
Spivack Phyllis G.
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