Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-06-18
2002-12-03
Ford, John M. (Department: 1609)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S256000, C546S257000, C546S258000, C546S167000, C546S113000, C546S121000, C546S261000, C546S268100, C546S268400, C546S269700, C546S270400, C546S271100, C546S271400, C546S272700, C546S274100, C546S276400, C546S283400, C546S282100, C546S280400, C546S280100, C546S275400, C544S333000, C544S405000, C544S124000, C544S360000, C544S264000, C544S266000, C514S256000, C514S314000, C514S338000, C514S231500, C514S232200, C514S252010
Reexamination Certificate
active
06489344
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to new pyrimidine and pyridine derivatives that inhibit the activity of glycogen synthase kinase 3 (GSK3) and to pharmaceutical compositions containing the compounds and to the use of the compounds and compositions, alone or in combination with other pharmaceutically active agents. The compounds and compositions provided by the present invention have utility in the treatment of disorders mediated by GSK3 activity, such as diabetes, Alzheimer's disease and other neurodegenerative disorders, obesity, atherosclerotic cardiovascular disease, essential hypertension, polycystic ovary syndrome, syndrome X, ischemia, especially cerebral ischemia, traumatic brain injury, bipolar disorder, immunodeficiency and cancer.
BACKGROUND OF THE INVENTION
Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase for which two isoforms, &agr; and &bgr;, have been identified. Woodgett,
Trends Biochem, Sci.,
16:177-81 (1991). Both GSK3 isoforms are constitutively active in resting cells. GSK3 was originally identified as a kinase that inhibits glycogen synthase by direct phosphorylation. Upon insulin activation, GSK3 is inactivated, thereby allowing the activation of glycogen synthase and possibly other insulin-dependent events, such glucose transport. Subsequently, it has been shown that GSK3 activity is also inactivated by other growth factors that, like insulin, signal through receptor tyrosine kinases (RTKs). Examples of such signaling molecules include IGF-1 and EGF. Saito et al.,
Biochem. J.,
303:27-31 (1994); Welsh et al.,
Biochem. J.
294:625-29 (1993); and Cross et al.,
Biochem. J.,
303:21-26 (1994).
Agents that inhibit GSK3 activity are useful in the treatment of disorders that are mediated by GSK3 activity. In addition, inhibition of GSK3 mimics the activation of growth factor signaling pathways and consequently GSK3 inhibitors are useful in the treatment of diseases in which such pathways are insufficiently active. Examples of diseases that can be treated with GSK3 inhibitors are described below.
Diabetes
Type 2 diabetes is an increasingly prevalent disease of aging. It is initially characterized by decreased sensitivity to insulin and a compensatory elevation in circulating insulin concentrations, the latter of which is required to maintain normal blood glucose levels. Increased insulin levels are caused by increased secretion from the pancreatic beta cells, and the resulting hyperinsulinemia is associated with cardiovascular complications of diabetes. As insulin resistance worsens, the demand on the pancreatic beta cells steadily increases until the pancreas can no longer provide adequate levels of insulin, resulting in elevated levels of glucose in the blood. Ultimately, overt hyperglycemia and hyperlipidemia occur, leading to the devastating long-term complications associated with diabetes, including cardiovascular disease, renal failure and blindness. The exact mechanism(s) causing type 2 diabetes are unknown, but result in impaired glucose transport into skeletal muscle and increased hepatic glucose production, in addition to inadequate insulin response. Dietary modifications are often ineffective, therefore the majority of patients ultimately require pharmaceutical intervention in an effort to prevent and/or slow the progression of the complications of the disease. Many patients can be treated with one or more of the many oral anti-diabetic agents available, including sulfonylureas, to increase insulin secretion. Examples of sulfonylurea drugs include metformin for suppression of hepatic glucose production, and troglitazone, an insulin-sensitizing medication. Despite the utility of these agents, 30-40% of diabetics are not adequately controlled using these medications and require subcutaneous insulin injections. Additionally, each of these therapies has associated side effects. For example, sulfonylureas can cause hypoglycemia and troglitazone can cause severe hepatoxicity. Presently, there is a need for new and improved drugs for the treatment of prediabetic and diabetic patients.
As described above, GSK3 inhibition stimulates insulin-dependent processes and is consequently useful in the treatment of type 2 diabetes. Recent data obtained using lithium salts provides evidence for this notion. The lithium ion has recently been reported to inhibit GSK3 activity. Klein et al.,
PNAS
93:8455-9 (1996). Since 1924, lithium has been reported to have antidiabetic effects including the ability to reduce plasma glucose levels, increase glycogen uptake, potentiate insulin, up-regulate glucose synthase activity and to stimulate glycogen synthesis in skin, muscle and fat cells. However, lithium has not been widely accepted for use in the inhibition of GSK3 activity, possibly because of ifs documented effects on molecular targets other than GSK3. The purine analog 5-iodotubercidin, also a GSK3 inhibitor, likewise stimulates glycogen synthesis and antagonizes inactivation of glycogen synthase by glucagon and vasopressin in rat liver cells. Fluckiger-Isler et al.,
Biochem J
292:85-91 (1993); and Massillon et al.,
Biochem J
299:123-8 (1994). However, this compound has also been shown to inhibit other serine/threonine and tyrosine kinases. Massillon et al.,
Biochem J
299:123-8 (1994).
Alzheimer's Disease
GSK3 is also involved in biological pathways relating to Alzheimer's disease (AD). The characteristic pathological features of AD are extracellular plaques of an abnormally processed form of the amyloid precursor protein (APP), so called &bgr;-amyloid peptide (&bgr;-AP) and the development of intracellular neurofibrillary tangles containing paired helical filaments (PHF) that consist largely of hyperphosphorylated tau protein. GSK3 is one of a number of kinases that have been found to phosphorylate tau protein in vitro on the abnormal sites characteristic of PHF tau, and is the only kinase also demonstrated to do this in living cells and in animals. Lovestone et al.,
Current Biology
4:1077-86 (1994); and Brownlees et al.,
Neuroreport
8: 3251-3255 (1997). Furthermore, the GSK3 kinase inhibitor, LiCl, blocks tau hyperphosphorylation in cells. Stambolic et al.,
Current Biology
6:1664-8 (1996). Thus GSK3 activity may contribute to the generation of neurofibrillary tangles and consequently to disease progression. Recently it has been shown that GSK3&bgr; associates with another key protein in AD pathogenesis, presenillin 1 (PS1). Takashima et.,
PNAS
95:9637-9641 (1998). Mutations in the PS1 gene lead to increased production of &bgr;-AP, but the authors also demonstrate that the mutant PS1 proteins bind more tightly to GSK3&bgr; and potentiate the phosphorylation of tau, which is bound to the same region of PS1.
Interestingly it has also been shown that another GSK3 substrate, &bgr;3-catenin, binds to PS1. Zhong et al.,
Nature
395:698-702 (1998). Cytosolic &bgr;-catenin is targeted for degradation upon phosphorylation by GSK3 and reduced &bgr;-catenin activity is associated with increased sensitivity of neuronal cells to &bgr;-AP induced neuronal apoptosis. Consequently, increased association of GSK3&bgr; with mutant PS1 may account for the reduced levels of &bgr;-catenin that have been observed in the brains of PS1-mutant AD patients and to the disease related increase in neuronal cell-death. Consistent with these observations, it has been shown that injection of GSK3 antisense but not sense, blocks the pathological effects of &bgr;-AP on neurons in vitro, resulting in a 24 hr delay in the onset of cell death and increased cell survival at 1 hr from 12 to 35%. Takashima et al.,
PNAS
90:7789-93. (1993). In these latter studies, the effects on cell-death are preceded (within 3-6 hours of &bgr;-AP administration) by a doubling of intracellular GSK3 activity, suggesting that in addition to genetic mechanisms that increase the proximity of GSK3 to its substrates, &bgr;-AP may actually increase GSK3 activity. Further evidence for a role for GSK3 in AD is provided by the observation that the protein expression level (b
Boyce Rustum S.
Brown Sean P.
Goff Dane A.
Harrison Stephen D.
Johnson Kirk W.
Blackburn Robert P.
Chiron Corporation
Ford John M.
Lentini David P.
Shelton Dennis K.
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