Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-07-16
2003-10-07
Kifle, Bruck (Department: 1609)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S520000, C544S343000, C544S346000, C544S349000
Reexamination Certificate
active
06630472
ABSTRACT:
TECHNICAL FIELD AND INDUSTRIAL APPLICABILITY OF THE INVENTION
The present invention relates to methods and pharmaceutical compounds and compositions for stimulating neurite outgrowth in nerve cells leading to nerve regeneration. More particularly, the compositions comprise compounds that inhibit the peptidyl-prolyl isomerase (rotamase) enzyme activity associated with the FK-506 binding protein (FKBP). The methods comprise treating nerve cells with compositions comprising the rotamase-inhibiting compound. The methods of the invention can be used to promote repair of neuronal damage caused by disease or physical trauma.
BACKGROUND OF THE INVENTION
Immunophilins are a family of soluble proteins that serve as receptors for important immunosuppressant drugs such as cyclosporin A, FK-506 and rapamycin. An immunophilin of particular interest is the FK-506 binding protein (FKBP). For a review of the role of immunophilins in the nervous system, see Solomon et al., “Immunophilins and the Nervous System,”
Nature Med
., 1(1), 32-37 (1995).
The 12-kiloDalton FK-506 binding protein, FKBP12, binds FK-506 with high affinity. Such binding has been directly measured using microcalorimetry and radiolabeled FK-506, e.g., [
3
H]dihydro-FK-506 (see Siekierka et al.,
Nature
, 341, 755-57 (1989); and U.S. Pat. No. 5,696,135 to Steiner et al.) and 32-[1-
14
C]-benzoyl-FK-506 (see Harding et al.,
Nature
, 341, 758-60 (1989)). Binding affinity of other compounds for FKBP can be determined directly by microcalorimetry or from competitive binding assays using either tritiated or
14
C-labelled FK-506, as described by Siekierka et al. or Harding et al.
FK-506-binding protein FKBP12 participates in a variety of significant cellular functions. FKBP12 catalyzes cis-trans isomerization of peptidyl-prolyl linkages. This peptidyl-prolyl isomerase enzyme activity is also referred to as rotamase activity. Such activity is readily assayed by methods known in the art (see Fischer et al.,
Biochim. Biophys. Acta
791, 87 (1984); Fischer et al.,
Biomed. Biochim. Acta
43, 1101 (1984); and Fischer et al.,
Nature
337, 476-478 (1989)). U.S. Pat. Nos. 5,192,773 and 5,330,993 to Armistead et al. report FKBP binding affinities that were correlated with rotamase-inhibiting activities for many compounds.
FK-506 and compounds that bind FKBP competitively with FKBP stimulate outgrowth of neurites (axons) in nerve cells (see U.S. Pat. No. 5,696,135 to Steiner et al.). Lyons et al. (
Proc. Natl. Acad, Sci, USA
, 91, 3191-95 (1994)) demonstrated that FK-506 acts to enhance or potentiate the effectiveness of nerve growth factor (NGF) in stimulating neurite outgrowth in a rat pheochromocytoma cell line. The mechanism of stimulation of such neurite outgrowth appears to be 10- to 100-fold potentiation of the action of nerve growth factor.
Potency for inhibition of the peptidyl-prolyl isomerase (rotamase) enzyme activity of FKBP by FK-506, and by compounds that competitively inhibit FK-506 binding to FKBP, empirically correlates with activity for stimulation of neurite outgrowth. Because of the close correlation between rotamase inhibition and neurotrophic action, it has been proposed that the rotamase may convert a protein substrate into a form that promotes neural growth (see U.S. Pat. No. 5,696,135). For example, it has been found that FKBP12 forms bound complexes with the intracellular calcium ion channels—the ryanodine receptor (RyR) and the inositol 1,4,5-triphosphate receptor (IP
3
R) (Jayaraman et al.,
J. Biol. Chem
., 267, 9474-9477 (1992); Cameron et al.,
Proc. Natl. Acad. Sci, USA
, 92, 1784-1788 (1995)), helping to stabilize calcium release. For both the RyR and the IP
3
R, it has been demonstrated that FK-506 and rapamycin are capable of dissociating FKBP12 from these receptors. In both cases, the “stripping” off of FKBP12 leads to increased leakiness of the calcium channels and lower intracellular calcium concentrations. It has been suggested that calcium flux may be associated with stimulation of neurite outgrowth.
In addition, FK-506-FKBP bound complexes bind to and inhibit calcineurin, a cytoplasmic phosphatase. The phosphatase activity of calcineurin is necessary for dephosphorylation and subsequent translocation into the nucleus of nuclear factor of activated T-cells (NF-AT) (see Flanagan et al.,
Nature
, 352, 803-807 (1991)). NF-AT is a transcription factor that initiates interleukin-2 gene activation, which in turn mediates T-cell proliferation; these steps are important to the activation of an immune response. Calcineurin-inhibiting activity is correlated with the immunosuppressant activity of FK-506 and related compounds.
Calcineurin inhibition, however, does not correlate with the stimulation of neurite outgrowth. Therefore, compounds that are potent inhibitors of rotamase but not strong inhibitors of calcineurin are desired since they should be neurotrophic but non-immunosuppressive.
Such neurotrophic agents desirably find use in augmenting neurite outgrowth, and hence in promoting neuronal growth and regeneration in various pathological situations where neuronal repair can be facilitated, including peripheral nerve damage caused by injury or diseases such as diabetes, brain damage associated with stroke, and for the treatment of neurological disorders related to neurodegeneration, including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS). Further, such use is preferably without the associated effect of immunosuppression, since long-term use of immunosuppressants is associated with side effects such as kidney toxicity, neurological deficits, and vascular hypertension.
Various inhibitors of rotamase enzyme activity, FKBP-binding compounds, or immunomodulating compounds are known. See, e.g., U.S. Pat. Nos. 5,192,773, 5,330,993, 5,516,797, 5,612,350, 5,614,547, 5,622,970, 5,654,332, 5,665,774, 5,696,135, and 5,721,256. See also International Publication Nos. WO 96/41609, WO 96/40633, and WO 96/40140.
In view of the variety of disorders that may be treated by stimulating neurite outgrowth and the relatively few potent FKBP12-binding compounds that are known to possess this property, there remains a need for additional neurotrophic, rotamase-binding compounds. Such compounds will desirably have physical and chemical properties suitable for use in pharmaceutical preparations, e.g., bioavailability, half-life, and efficient delivery to the active site. In view of the desired properties, small organic molecules are preferred over proteins. Furthermore, such compounds will desirably lack significant immunosuppressive activity.
SUMMARY OF THE INVENTION
It is therefore an object of the invention to provide small-molecule neurotrophic agents. An additional object is to achieve rotamase-binding compounds that are non-immunosuppressive agents. It is a further object of the invention to provide effective processes for synthesizing such compounds as well as useful intermediates therefor. Another object of the invention is to provide methods for treating patients having neurological trauma or disorders as a result of, or associated with, conditions that include (but are not limited to) neuralgias, muscular dystrophy, Bell's palsy, myasthenia gravis, Parkinson's disease, Alzheimer's disease, multiple sclerosis, ALS, stroke and ischemia associated with stroke, neural parapathy, other neural degenerative diseases, motor neuron diseases, and nerve injuries including spinal cord injuries.
Such objects have been achieved by the rotamase-binding agents of the present invention, which may be used to stimulate the growth and regeneration of neurons. The administration of these agents to individuals requiring therapeutic stimulation of neuronal growth and regeneration provides effective therapies in various pathological situations where neuronal repair can be facilitated, including peripheral nerve damage caused by injury or disease such as diabetes, brain damage associated with stroke, and for the treatment of neurological disorders related to neuro
Kalish Vincent
Katoh Susumu
Kawakami Hiroshi
Linton Maria Angelica
Tada Hiroki
Catania Richard L.
Ginsburg Paul H.
Kifle Bruck
Pfizer Inc
Richardson Peter C.
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