Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-12
2003-04-29
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S046000, C514S258100, C514S262100, C514S263370, C514S266400, C544S242000, C544S239000, C544S253000, C544S256000, C544S262000, C544S264000, C544S265000, C536S026130
Reexamination Certificate
active
06555545
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods and compositions for treating and preventing hepatic fibrosis and cirrhosis as well as fatty liver.
BACKGROUND OF THE INVENTION
Adenosine is a nucleoside with wide distribution in the body. Adenosine mediates a broad array of physiological responses, including central nervous system sedation, inhibition of platelet aggregation and vascular smooth muscle vasodilation. These effects occur largely through interaction of adenosine with one of four types of adenosine receptors.
Adenosine thus perhaps represents a general regulatory substance, since no particular cell type or tissue appears uniquely responsible for its formation. In this regard, adenosine is unlike various endocrine hormones. There is no evidence for storage and release of adenosine from nerve or other cells. Thus, adenosine is unlike various neurotransmitter substances.
Adenosine, like the prostaglandins, may be characterized as a physiological regulator. In both cases the enzymes involved in the metabolic formation are ubiquitous and appear to be responsive to alterations in the physiological state of the cell. Receptors for adenosine, like those for prostaglandins, are very widespread.
Adenosine receptors comprise a group of cell surface molecules that mediate the physiologic effects of adenosine. Recent reviews include Stiles, G. F.,
Trends in Pharmacol. Sci.
7:485-490 (1986); Ramkumar, V. et al.,
Prog. Drug Res.
32:195-247 (1988); Olah, M. E. et al.,
Anu. Rev. Physiol.
54:211-225 (1992); Stiles, G. L.
J. Biol. Chem.
267:6451-6454 (1992); Jacobson, K. A. et al.,
J. Med. Chem.
35:407-422 (1992). This family of receptors was originally classified as P1 or P2 purinergic receptors, dependent upon their preferential interactions with adenosine (P1) or ATP (P2) (Burnstock et al., in
Cell Membrane Receptors of Drugs and Hormones
, Straub et al., eds., Raven Press, New York, 1978, pp. 107-118). The P1 sites were further subdivided into A
1
, A
2A
, A
2B
, and A
3
adenosine receptors based on their differential selectivity of adenosine analogues and molecular structure (Van Calker, D. et al.,
J. Neurochem
33:999-1005 (1979); Londos, C. et al.
Proc. Natl. Acad. Sci. USA
77:2552-2554 (1980); Ralevic et al.,
Pharmacological reviews
50(3):413-92 (1998); Poulsen et al.,
Bioorganic
&
Medicinal Chemistry
6(6):619-41 (1998); Khakh et al.,
Trends in Pharmacological Sciences
19(2): 39-41 (1998)). The A
1
adenosine receptor, which is inhibitory to adenylyl cyclase, exhibits the potency order (R)-PIA>NECA>(S)-PIA. The A
2
adenosine receptor, which is stimulatory to adenylyl cyclase, has a different potency order were NECA>(R)-(PIA)>(S)-PIA. ((R)-PIA is N6-phenylisopropyladenosine; (S)-PIA is N6-(S)-phenylisopropyladenosine; NECA is N-ethyl adenosine-5′-uronic acid). Both the A
1
and the A
2
adenosine receptors are widely distributed in the central nervous system and peripheral tissues (Ramkumar, V. et al., supra).
Additional information on adenosine receptors can be found in Ralevid et al.,
Pharmacological reviews
50(3):413-92, 1998; Poulsen et al.,
Bioorganic
&
Medicinal Chemistry
6(6):619-41, 1998 and Khakh et al.,
Trends in Pharmacological Sciences
19(2):39-41, 1998.
Four different adenine receptors have been claimed and their sequence is known. Until relatively recently, no truly useful radio ligand was available for characterizing the A
2
adenosine receptors. Demonstration of adenosine receptors in smooth muscle was made primarily by functional assays, for example, adenosine stimulation of adenylyl cyclase activity via A
2
receptors in vascular smooth muscle cells in culture (Anand-Srivastava, M. B. et al.,
Biochem. Biophys. Res. Commun.
108: 213-219 (1982); Anand-Srivastava , M. B. et al.,
Life Sci.
37: 857-867 (1985)). However, the concentrations of adenosine required to elevate cAMP were higher than those required of full vasorelaxation in vivo (Berne, R. M.,
Circ. Res.
47:807-813 (1980); Herlihy, J. T. et al.,
Am. J. Physiol.
230:1239-1243 (1976)). One cell line which has proved useful of studying A1 and A2 adenosine receptors (Ramkumar, V. et al.,
Molec. Pharmacol.
37:149-156 (1990) is the DDT1 MF-2 line, a smooth muscle cell line derived from a steroid-induced leimyosacroma of the vas deferens of an adult Syrian hamster (Norris, J. S. et al.,
Nature
248:422-424 (1974)).
Recently, two compounds were found to possess selective high affinity against radio ligands of the A
2
receptor: [3H]CGS 21680 (Jarvis, M. R. et al.,
J. Pharmacolo. Exp. Their
251:888-893 (1989) and 125I-PAPA-APEC, the full chemical name of which is {2-3(2(2-(4-amino phenyl)methyl carbonyl-amino)ethylaminocarbonyl)ethyl]phenyl}ethylamino-5′-N-ethylcarboxamindoadenosine (Barrington, W. W. et al.,
Proc. Natl. Acad. Sci. USA
86:6572-6576 (1989)). Use of such ligands allowed identification of the A
2
binding subunit as a 45 kDa protein (on SDS-PAGE) that was clearly distinguishable from the 38 kDa A
1
binding subunit. Use of the azide derivative of
125
-I-PAPA-APEC, a direct photo affinity probe of the A
2
receptor, made it possible to demonstrate that the A
2
binding subunit is a glycoprotein clearly different from the A
1
receptor glycoprotein (Barrington, W. W. et al.,
Mol. Pharmacol.
38:177-183 (1990)). The A
2
adenosine receptor has a single carbohydrate chain of either the complex or high mannose type.
Useful adenosine receptor agonists, in particular those with selectivity of the A
2
receptor, are well known in the art. These include 2-substituted adenosine-5′-carboxamide derivatives (Hutchison, U.S. Pat. Nos. 4,968,697 and 5,034,381) and N9-cyclopentyl-substituted adenine derivatives (Chen et al., U.S. Pat. No. 5,063,233). These patents are hereby incorporated by reference in their entireties.
Adenosine and its analogues interact with neutrophils in inflammatory responses. While neutrophils are essential for limiting the spread of infection by a variety of microbes, stimulated neutrophils may damage injured tissues while en route to sites of infection or inflammation. Release of adenosine is one mechanism by which normal cells may protect themselves from activated neutrophils. Thus, one important action of adenosine and its analogues is the inhibition of generation of toxic oxygen products, including O
2
−
and H
2
O
2
, by interacting with A
2
receptors on the neutrophil (Cronstein, B. N. et al.,
J. Immunol.
135:1366-1371 (1985); Roberts, P. A. et al.,
Biochem. H.
227:669-674 (1985); Schrier, D. J. et al.,
J. Immunol.
137:3284-3289 (1989); Iannone, M. A. et al.,
Fed. Proc.
44:580 (abstr.) (1985)). Adenosine promotes neutrophil chemotaxis via the A
1
receptor (Cronstein, B.Nalet supra; Rose, F. R. et al.,
J. Exp. Med.
167:1186-1194 (1989)). Adenosine receptor ligation regulates inflammatory responses of neutrophils triggered by immune complexes acting through the Fc&ggr; receptor (Salmon, J. E.,
Immuno.
145:2235-2240 (1990)). Specifically, activation of A
2
receptors inhibited these inflammatory responses, whereas activation of A
1
receptors was stimulatory. These authors noted an important role of adenosine at picomolar concentrations as a promoter, and at micro molar concentrations as an inhibitor, of neutrophil responses elicited by immune complexes.
Interestingly, the immunosuppressive drug methotrexate, at low concentrations, acts as an anti-inflammatory agent at least in part due to its capacity to induce adenosine release by connective tissue cells such as dermal fibroblasts or umbilical vein endothelial cells. The released adenosine interacted with the neutrophil adenosine receptors (Cronstein, B. N. et al.,
Proc. Natl. Sci. USA
88:2441-2445 (1991)).
The nonselective adenosine receptor agonist, 2-chloroadenosine, inhibited adherence of stimulated neutrophils to endothelium, thus protecting the endothelium from inflammatory effects (Cronstein, B. N. et al.,
J. Clin, Invest.
78:760-770 (1986)). More recently, work from the present inventors
Chan Edwin
Cronstein Bruce N.
Khare Devesh
New York University
Wilson James O.
LandOfFree
Adenosine A2A receptor antagonists for treating and... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Adenosine A2A receptor antagonists for treating and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Adenosine A2A receptor antagonists for treating and... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3105402