Selective antagonists of A2B adenosine receptors

Details Selective antagonists of A2B adenosine receptors Selective antagonists of A2B adenosine receptors

2000-08-28

2004-11-09

Berch, Mark L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S234200, C514S263340, C514S263220, C544S272000, C544S118000

Reexamination Certificate

active

06815446

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel pharmaceutical compounds useful as selective antagonists of the A
2B
adenosine receptor. Furthermore, the present invention relates to novel pharmaceutical compositions useful for treating certain indications including asthma and diarrhea. The present invention also relates to novel methods of treating certain indications including asthma and diarrhea.
BACKGROUND OF THE INVENTION
There is substantial evidence that adenosine modulates many physiological processes. Its actions are mediated by interaction with specific cell membrane receptors. Four types of adenosine receptors have been identified: A
1
, A
2A
, A
2B
and A
3
. All four subtypes have been cloned from human tissue. Adenosine receptors have the seven transmembrane domain structure typical of G protein-coupled receptors. Adenosine receptors are widely distributed throughout the body and are probably present in every cell.
Adenosine receptors were initially classified by the ability to inhibit (A
1
) or activate (A
2
and A
2B
) adenylate cyclase. A
3
receptors also inhibit adenylate cyclase. Modulation of adenylate cyclase is mediated through coupling to G
s
and G
i
guanine-nucleotide regulatory proteins. It is now known that adenosine receptors are also coupled to other intracellular signaling pathways. A
1
and A
3
receptors, for example, can couple to phospholipase C; A
1
receptors are also coupled to K channels. A
2B
receptors are also coupled to Gq and mediate activation of PLC, Ras and MAP kinases.
Substituted xanthines represent the most potent class of adenosine-receptor antagonists reported to date. See Katsushima et al., Structure-Activity Relationships of 8-cycloalkyl-1,3-dipropylxanthines as Antagonists of Adenosine Receptors, J. Med. Chem., 33:1906-1910 (1990); and Martinson et al., Potent Adenosine Receptor Antagonists that are Selective for the A
1
Receptor Subtype, Molecular Pharmacology, 31:247-252 (1987).
The study of A
2B
receptors has been hampered by the lack of selective pharmacological probes. Nonetheless, A
2B
receptors can be distinguished from A
2A
receptors by their low affinity and their distinct rank order of potency for agonists. NECA (5′-N-ethylcarboxamidoadenosine) is one of the most potent agonist at A
2B
receptors, but is also effective at A
2A
receptors. On the other hand, the agonist CGS 21680 (4-((N-ethyl-5′carbamoyladenos-2-yl)-aminoethyl)-phenylpropionic acid) is virtually inactive at A
2B
receptors, whereas it is as potent as NECA at A
2A
receptors. The lack of effectiveness of CGS 21680 has proven useful in the functional characterization of A
2B
receptors. A
2B
receptors also have a very low affinity to the A
3
selective agonists IB-MECA and N
6
-benzyl NECA. These agonists can, therefore, be used to differentiate between A
2B
and A
3
receptors. In summary, A
2B
receptors can be identified by their unique rank order of potency for agonists NECA>PIA≧IB-MECA>CGS-21680.
Whereas A
2B
receptors have, in general, a lower affinity for agonists compared to other receptors subtypes, this is not true for antagonists. The structure activity relationship of adenosine antagonists on A
2B
receptors has not been fully characterized, but at least some xanthines are as or more potent antagonists of A
2B
receptor subtypes than of other subtypes. In particular, DPSPX (1,3-dipropyl-8-sulphophenylxanthine), DPCPX and DPX (1,3 diethyl-phenylxanthine) have affinities in the mid to high nM range.
The present inventors have recognized that A
2B
receptors modulate important physiological processes. As stated by Feoktistov et al., Adenosine A
2B
Receptors as Therapeutic Targets, Drug Dev Res 45:198; A
2B
receptors have been implicated in mast cell activation, asthma, vasodialation, regulation of cell growth, intestinal function, and modulation of neurosecretion. Also see Feoktistov et al. Trends Pharmacol Sci 19:148-153.
Methods of mast cell activation, treating and/or preventing asthma and vasodialation, regulation of cell growth and intestinal function, and modulation of neurosecretion are all objects of the present invention.
As stated above, A
2B
receptors modulate important physiological processes. For example, A
2B
receptors are found in the colon in the basolateral domains of intestinal epithelial cells, and increase chloride secretion. Selective A
2B
antagonists with poor gastrointestinal absorption can also be useful in blocking intestinal chloride secretion. Thus, it is an object of the present invention to prevent and/or treat inflammatory gastrointestinal tract disorders including diarrhea.
Additionally, there are vascular beds in which NECA produces profound vasodilation. Based on reasonable confirmation that A
2B
receptors mediate vasodilation in the pulmonary circulation, an object of the present invention is to prevent and/or treat cardiac diseases.
A
2B
receptors are also present in cultured vascular smooth muscle cells and have been found to inhibit their growth. Since impaired adenosine mechanisms may play a role in the vascular remodeling process observed in atherosclerosis and hypertension, an object of the present invention is to prevent and/or treat atherosclerosis and hypertension.
A
2B
receptors are also present in endothelial cells and have been found to stimulate their growth. Since this will lead to growth of new blood vessels (angiogenesis). An object of this invention is to prevent and/or treat diseases characterized by abnormal blood vessel growth, such as diabetic retinopathy and cancer.
There is evidence that A
2B
receptors modulate mast cell function and that A
2B
receptors are present in mouse bone marrow-derived mast cells. A
2B
receptors have been shown to produce direct activation of HMC-1 cells, a cell line with phenotypic characteristics of human lung mast cells. This process involved activation of PLC through Gq proteins, and activation of MAP kinasis, intracellular processes not previously described for A
2
receptors. Virtually identical findings have been reported in a dog mastocytoma cells line. Evidence based on the research of the present inventors, using immunofluorescence techniques with a specific chicken anti-human A
2B
antibody, indicates the presence of A
2B
receptors in human lung mast cells obtained from asthmatics by bronchoalveolar lavage cells. Thus, an object of the present invention is to prevent and/or treat asthma. Asthma continues to be a substantial medical problem that affects approximately 5-7% of the population. Despite advances in its treatment, the prevalence of asthma emergency department visits, hospitalizations, and mortality related to the disease, all appear to be on the rise.
Additionally adenosine treatments such as inhaled adenosine provokes bronchoconstriction in asthmatics, but not in normals. This process involves mast cell activation because it is associated with the release of mast cell mediators, including histamine, PGD2-&bgr;-hexosaminidase and tryptase, and because it can be blocked by specific histamine H
1
blockers and chromolyn sodium. Furthermore, adenosine has been shown to potentiate activation of purified human lung mast cells. The low affinity of this process suggests the involvement of A
2B
receptors. Given that inhaled adenosine has no effect in normals, there appears to be an intrinsic difference in the way adenosine interacts with mast cells from asthmatics. The in vitro response produced by A
2B
receptors in HMC-1 cells and in dog mastocytoma cells appears to mimic in vivo responses to inhaled adenosine in asthmatics, inasmuch as adenosine provokes mast cells activation in these cell lines as it does in asthmatics. Thus, an object of the present invention is a method of modulating mast cell function or activation of human lung cells.
Theophylline remains an effective antiasthmatic agent even though it is a poor adenosine receptor antagonist. However, considerable plasma levels are needed for it to be effective. Additionally, Theophylline also has substantial side effects, most of wh

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