Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-12-01
2003-04-08
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S227500, C514S227800, C514S231200, C514S231500, C514S316000, C514S317000, C514S318000, C514S319000, C544S059000, C544S060000, C544S106000, C544S111000, C546S192000, C546S193000, C546S195000
Reexamination Certificate
active
06544987
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. For example, the compositions comprise compounds that inhibit the peptidyl-prolyl isomerase (rotamase) enzyme activity associated with the FK-506 binding proteins (FKBP), such as FKBP 12 and FKBP 52. 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
Inmunophilins 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 are the FK-506 binding proteins (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).
Such neurotrophic agents should also be useful for the treatment of memory impairment, for the treatment of hair loss, for the treatment of hearing loss, and for the treatment of vision disorder. See WO 00/16603 and WO 00/32588. 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; 5,721,256; 5,798,355; 5,786,378; 5,846,979; 5,801,187; 5,801,197 and 6,080,753. See also EP 947,506 and International Publication Nos. WO 96/41609, WO 96/40633, WO 96/40140, WO 98/29116, WO 98/29117, WO 97/14439, WO 98/37882, WO 99/45006, WO 00/27811, WO 00/09102, WO 00/05232, WO 00/46181 and WO 99/6251.
In view of the variety of disorders that may be treated by stimulating neurite outgrowth and the relatively few neurotropic agents having an affinity for FKBP-type immunophilins, there remains a need for additional neurotrophic agents. In particular, there is a need for those neurotropic agents that are potent inhibitors of the enzyme activity and especially of the cis-trans propyl isomerase (rotamase) activity of the FKBP-type immunophilins, particularly the immunophilin FKBP-12. 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 not significantly inhibit the protein phosphatase calcineurin and therefore lack any significant immunosuppressive activity.
According to International Publication Nos. WO 00/46181 and WO 00/46222, binding to FKBP is not necessary for neuronal activity.
SUMMARY OF THE INVENTION
It is therefore an object of the invention to provide small-molecule neurotrophic compounds, preferably through affinity for FKBP-type immunophilins. Once bound to these proteins, the neurotrophic compounds are potent inhibitors of the enzyme activity associated with immunophilin proteins, particularly rotamase enzyme activity. An additional object is to provide inhibitor compounds of the present invention that do not exert any significant immunosuppressive activity in addition to their neurotrophic activity. It is a further object
Dong Liming
Guo Chuangxing
Hou Xinjun J.
Vanderpool Darin
Villafranca Jesus Ernest
Ginsburg Paul H.
Ling Lorraine B.
Richardson Peter C.
Shah Mukund J.
Truong Tamthom N.
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