Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-04-10
2003-11-04
Rao, Deepak (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S235800, C514S252190, C514S275000, C544S060000, C544S122000, C544S331000
Reexamination Certificate
active
06642227
ABSTRACT:
TECHNICAL FIELD OF INVENTION
The present invention relates to inhibitors of protein kinase, especially c-Jun N-terminal kinases (JNK) and the Src-family of kinases, including Lck, which are members of the mitogen-activated protein (MAP) kinase family. JNK, Src, and Lck have been implicated in a number of different human diseases. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing those compositions in the treatment and prevention of various disorders in which JNK, Src, and Lck play a role.
BACKGROUND OF THE INVENTION
Mammalian cells respond to extracellular stimuli by activating signaling cascades that are mediated by members of the mitogen-activated protein (MAP) kinase family, which include the extracellular signal regulated kinases (ERKs), the p38 MAP kinases and the c-Jun N-terminal kinases (JNKs). MAP kinases (MAPKs) are activated by a variety of signals including growth factors, cytokines, UV radiation, and stress-inducing agents. MAPKs are serine/threonine kinases and their activation occur by dual phosphorylation of threonine and tyrosine at the Thr-X-Tyr segment in the activation loop. MAPKs phosphorylate various substrates including transcription factors, which in turn regulate the expression of specific sets of genes and thus mediate a specific response to the stimulus.
One particularly interesting kinase family are the c-Jun NH
2
-terminal protein kinases, also known as JNKs. Three distinct genes, JNK1, JNK2, JNK3 have been identified and at least ten different splicing isoforms of JNKs exist in mammalian cells [Gupta et al.,
EMBO J.,
15:2760-70 (1996)]. Members of the JNK family are activated by proinflammatory cytokines, such as tumor necrosis factor-&agr; (TNF&agr;) and interleukin-1 &bgr; (IL-1&bgr;), as well as by environmental stress, including anisomycin, UW irradiation, hypoxia, and osmotic shock [Minden et al.,
Biochemica et Biophysica Acta,
1333:F85-F104 (1997)].
The down-Stream substrates of JNKs include transcription factors c-Jun, ATF-2, Elk1, p53 and a cell death domain protein (DENN) [Zhang et al.
Proc. Natl. Acad. Sci. USA,
95:2586-91 (1998)]. Each JNK isoform binds to these substrates with different affinities, suggesting a regulation of signaling pathways by substrate specificity of different JNKs in vivo (Gupta et al., supra).
JNKs, along with other MAPKs, have been implicated in having a role in mediating cellular response to cancer, thrombin-induced platelet aggregation, immunodeficiency disorders, autoimmune diseases, cell death, allergies, osteoporosis and heart disease. The therapeutic targets related to activation of the JNK pathway include chronic myelogenous leukemia (CML), rheumatoid arthritis, asthma, osteoarthritis, ischemia, cancer and neurodegenerative diseases.
Several reports have detailed the importance of JNK activation associated with liver disease or episodes of hepatic ischemia [
Nat. Genet.
21:326-9 (1999);
FEBS Lett.
420:201-4 (1997);
J. Clin. Invest.
102:1942-50 (1998);
Hepatology
28:1022-30 (1998)]. Therefore, inhibitors of JNK may be useful to treat various hepatic disorders.
A role for JNK in cardiovascular disease such as myocardial infarction or congestive heart failure has also been reported as it has been shown JNK mediates hypertrophic responses to various forms of cardiac stress [
Circ. Res.
83:167-78 (1998);
Circulation
97:1731-7 (1998);
J. Biol. Chem.
272:28050-6 (1997);
Circ. Res.
79:162-73 (1996);
Circ. Res.
78:947-53 (1996);
J. Clin. Invest.
97:508-14 (1996)].
It has been demonstrated that the JNK cascade also plays a role in T-Cell activation, including activation of the IL-2 promoter. Thus, inhibitors of JNK may have therapeutic value in altering pathologic immune responses [
J. Immunol.
162:3176-87 (1999);
Eur. J. Immunol.
28:3867-77 (1998);
J. Exp. Med.
186:941-53 (1997);
Eur. J. Immunol.
26:989-94 (1996)].
A role for JNK activation in various cancers has also been established, suggesting the potential use of JNK inhibitors in cancer. For example, constitutively activated JNK is associated with HTLV-1 mediated tumorigenesis [
Oncogene
13:135-42 (1996)]. JNK may play a role in Kaposi's sarcoma (KS) because it is thought that the proliferative effects of bFGF and OSM on KS cells are mediated by their activation of the JNK signaling pathway [
J. Clin. Invest.
99:1798-804 (1997)]. Other proliferative effects of other cytokines implicated in KS proliferation, such as vascular endothelial growth factor (VEGF), IL-6 and TNF&agr;, may also be mediated by JNK. In addition, regulation of the c-jun gene in p210 BCR-ABL transformed cells corresponds with activity of JNK, suggesting a role for JNK inhibitors in the treatment for chronic myelogenous leukemia (CML) [
Blood
92:2450-60 (1998)].
JNK1 and JNK2 are widely expressed in a variety of tissues. In contrast, JNK3, is selectively expressed in the brain and to a lesser extent in the heart and testis [Gupta et al., supra; Mohit et al.,
Neuron
14:67-78 (1995); Martin et al.,
Brain Res. Mol. Brain Res.
35:47-57 (1996)]. JNK3 has been linked to neuronal apoptosis induced by kainic acid, indicating a role of JNK in the pathogenesis of glutamate neurotoxicity. In the adult human brain, JNK3 expression is localized to a subpopulation of pyramidal neurons in the CA1, CA4 and subiculum regions of the hippocampus and layers 3 and 5 of the neocortex [Mohit et al., supra]. The CA1 neurons of patients with acute hypoxia showed strong nuclear JNK3-immunoreactivity compared to minimal, diffuse cytoplasmic staining of the hippocampal neurons from brain tissues of normal patients [Zhang et al., supra]. Thus, JNK3 appears to be involved involved in hypoxic and ischemic damage of CA1 neurons in the hippocampus.
In addition, JNK3 co-localizes immunochemically with neurons vulnerable in Alzheimer's disease [Mohit et al., supra]. Disruption of the LNK3 gene caused resistance of mice to the excitotoxic glutamate receptor agonist kainic acid, including the effects on seizure activity, AP-1 transcriptional activity and apoptosis of hippocampal neurons, indicating that the JNK3 signaling pathway is a critical component in the pathogenesis of glutamate neurotoxicity (Yang et al.,
Nature,
389:865-870 (1997)].
Based on these findings, JNK signalling, especially that of JNK3, has been implicated in the areas of apoptosis-driven neurodegenerative diseases such as Alzheimer's Disease, Parkinson's Disease, ALS (Amyotrophic Lateral Sclerosis), epilepsy and seizures, Huntington's Disease, traumatic brain injuries, as well as ischemic and hemorrhaging stroke.
The Src-family of kinases are implicated in cancer, immune system dysfunction, and bone remodeling diseases. For general reviews, see Thomas and Brugge,
Annu. Rev. Cell Dev. Biol.
(1997) 13, 513; Lawrence and Niu,
Pharmacol. Ther.
(1998) 77, 81; Tatosyan and Mizenina,
Biochemistry
(Moscow) (2000) 65, 49; Boschelli et al.,
Drugs of the Future
2000, 25(7), 717, (2000).
Members of the Src family include the following eight kinases in mammals: Src, Fyn, Yes, Fgr, Lyn, Hck, Lck, Blk and Yrc. These are nonreceptor protein kinases that range in molecular mass from 52 to 62 kD. All are characterized by a common structural organization that is comprised of six distinct functional domains: Src homology domain 4 (SH4), a unique domain, SH3 domain, SH2 domain, a catalytic domain (SH1), and a C-terminal regulatory region. Tatosyan et al.
Biochemistry
(Moscow) 65, 49-58 (2000).
Based on published studies, Src kinases are considered as potential therapeutic targets for various human diseases. Mice that are deficient in Src develop osteopetrosis, or bone build-up, because of depressed bone resorption by osteoclasts. This suggests that osteoporosis resulting from abnormally high bone resorption can be treated by inhibiting Src. Soriano et al., Cell, 69, 551 (1992) and Soriano et al., C
Cao Jingrong
Gao Huai
Green Jeremy
Harrington Edmund
Ledeboer Mark
Rao Deepak
Robidoux Andrea L. C.
Vertex Pharmaceuticals Incorporated
Vertex Pharmaceuticals Incorporated
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