Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
2000-03-08
2004-05-11
Eyler, Yvonne (Department: 1646)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S006120, C435S007100, C435S069100, C435S069500, C435S252300, C436S501000, C514S002600, C514S260100, C530S350000, C536S023500, C544S284000, C544S291000
Reexamination Certificate
active
06733982
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to the discovery that selective alpha
1B
adrenergic receptor antagonists can be useful for the treatment of pain. In particular, the present invention relates to methods for screening compounds to identify an alpha
1B
adrenergic receptor ligand that binds to the alpha
1B
adrenergic receptor to provide an analgesic effect.
BACKGROUND
Alpha
1
adrenergic receptors are G-protein coupled transmembrane receptors that mediate various actions of the sympathetic nervous system through the binding of the catecholamines, epinephrine and norepinephrine. Currently, several subtypes of the alpha
1
adrenergic receptors are known to exist for which the genes have been cloned: alpha
1A
(previously known as alpha
1C
), alpha
1B
and alpha
1D
. The existence of an additional subtype, the alpha
1L
adrenergic receptor subtype, has been proposed; however, the gene for the alpha
1L
adrenergic receptor subtype has yet to be cloned. Although these subtypes can be pharmacologically distinguished, existing subtype-selective compounds are only moderately specific and may interact with more than one alpha
1
adrenergic receptor subtype. (See Giardina, D., et al.,
J. Med. Chem.,
1996, 39:4602-4607). Accordingly, therapeutic use of nonselective alpha
1
adrenergic receptor antagonists must be carefully monitored as such antagonists can produce significant undesirable side effects such as postural hypotension, sedation or depression, increased gastrointestinal motility and diarrhea, impaired ability to ejaculate, nasal stuffiness, akinesia and the like.
Compounds that interact more selectively with a particular alpha
1
adrenergic receptor subtype may prove clinically useful in providing more selective treatment of conditions and diseases associated with abnormal activity at the receptor subtype. For example, alpha
1
adrenergic receptor antagonists that can selectively ameliorate nociceptive and/or neurogenic pain without affecting blood pressure or causing postural hypotension, are desirable. Presently available alpha
1
adrenergic antagonists are either relatively nonselective with respect to the subtypes with which they interact or are not selective for the alpha
1B
adrenergic receptor subtype.
Selective alpha
1B
adrenergic receptor antagonists can also be useful in the treatment of CNS disorders including, but not limited to, anxiety, sleep disorders, and schizophrenia. (See, e.g., Bakshi et al. (1999)
Neuroscience
92:113-121; Carasso, et al. (1998)
Neuropharmacol.
37:401-404; and Acosta-Martinez, et al. (1999)
Neurochem. Int.
35:383-391.)
The present invention relates to the discovery of a preferred class of novel compounds that are selective alpha
1B
adrenergic receptor antagonists (see, commonly owned U.S. patent applications U.S. S.No. 60/124,781; filed on Mar. 17, 1999; U.S. S.No. 60/165,312, filed on Nov. 12, 1999; and U.S. Ser. No. 09/521,185, filed Mar. 8, 2000 by Coffen, et al. entitled “Oxazolone Derivatives and Uses Thereof,” filed herewith, the disclosure of which are incorporated by reference herein), and that alpha
1B
adrenergic receptor-selective compounds possess analgesic activity.
SUMMARY OF THE INVENTION
Accordingly, there is a need in the art for a method by which compounds can be identified having alpha
1B
adrenergic receptor-mediated analgesic activity.
It is a primary object of the invention to addressed the above-described need in the art.
It is another object of the invention to provide a method by which compounds can be screened to identify those that produce alpha
1B
adrenergic receptor-mediated analgesia.
It is still another object of the invention to provide compounds identified by the aforementioned method.
It is yet another object of the invention to provide a method of treating a subject to produce analgesia comprising administering to the subject in need of analgesia a therapeutically effective amount of a compound identified by the aforementioned method, or a pharmaceutically acceptable salt or hydrate thereof, or pharmaceutical composition comprising such a compound, or salt or hydrate thereof.
In one embodiment of the invention, a method for screening for compounds having alpha
1B
adrenergic receptor-mediated analgesic activity is provided. The method comprises (a) measuring the activity of a test compound in a first binding assay and (b) measuring activity of the test compound in at least one pain model, wherein (a) and (b) are done concurrently or consecutively in any order. The first binding assay comprises (i) providing a preparation of a cell that expresses an alpha
1B
adrenergic receptor, (ii) combining a test compound with the cell preparation, and (iii) measuring binding of the test compound to the cell preparation or the receptor. The test compound is also be evaluated in a second binding assay for its ability to bind to the alpha
1A
and/or alpha
1D
adrenergic receptor, and/or to other receptors, e.g., histamine receptors, dopamine receptors, and the like. A test compound is also evaluated for its ability to elicit an appropriate response in at least one pain model, e.g., the ability to reduce nociceptive or neurogenic pain. Optionally, test compounds are evaluated for other alpha
1
adrenergic receptor-mediated functional activity.
The invention includes a method of treating a subject for the production of analgesia. The phrases “production of analgesia” and “reduction of pain” are used interchangeably herein. In the method, a therapeutically effective amount of a compound identified by the method disclosed and claimed herein, or a pharmaceutically acceptable salt or hydrate thereof, is administered to a subject in need of a reduction of pain. The compound can be administered after a trauma that causes acute or chronic pain. Optionally, the compound, or a pharmaceutically acceptable salt or hydrate thereof, can be administered as a composition comprising one or more pharmaceutically acceptable additives, diluents, or carriers to form a pharmaceutical composition. In one embodiment, such a composition is a sustained release formulation.
In a further embodiment, the pharmaceutical composition can also include one or more compounds having at least one of antiinflammatory activity, analgesic activity, and anticonvulsant activity. Examples of other compounds include, but are not limited to the following: compounds used in the treatment of neuropathic pain including, but not limited to tricyclic antidepressants (e.g., amitriptyline, imipramine, desipramine), anti-convulsants (e.g., gabapentin, carbamazepine, phenytoin) and local anesthetics (e.g., mexiletine, lidocaine); and compounds used in the treatment of inflammatory pain including, but not limited to nonsteroidal antiinflammatory agents, (e.g., ibuprofen, naprosyn sodium, aspirin, diclofenac sodium, indomethacin, toletin), steroids (e.g., methylprednisone, prednisone), analgesics (e.g., acetaminophen), and opiates (e.g., tramadol, demerol, darvon, vicodin, fentanyl).
Administration of a selected compound is accomplished by conventional means including but not limited to oral, enteral, rectal, mucosal, percutaneous, and parenteral administration. In a preferred embodiment, the selected compound is administered orally.
In another aspect, the invention includes a pharmaceutical composition, comprising (a) a therapeutically effective amount of a compound identified by the method disclosed and claimed herein, or a pharmaceutically acceptable salt or hydrate thereof, and (b) a pharmaceutically acceptable additive, diluent, or carrier. In one embodiment, this composition is a sustained release formulation.
In another embodiment, the present invention encompasses a method of treating a subject suffering from a CNS disorder comprising administering to the subject a therapeutically effective amount of a compound identified by the method of screening disclosed or a pharmaceutically acceptable salt or hydrate thereof. In a further embodiment, the subject suffering from a CNS disorder is administered a therapeutically effective amou
Ford Anthony P. D. W.
Gogas Kathleen Ruth
Jacobson Lupita O.
Williams Timothy James
Brannock Michael
Eyler Yvonne
Hall Robert C.
Peries Rohan
Syntex (U.S.A.) LLC
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