Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-12-22
2004-06-29
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S369000, C514S364000, C514S376000, C514S277000, C514S299000, C514S367000, C514S370000, C514S569000, C514S725000
Reexamination Certificate
active
06756360
ABSTRACT:
BACKGROUND OF THE INVENTION
A combination therapy of an insulin sensitizer and an FBPase inhibitor is disclosed for the treatment of diabetes, and other diseases where the control of blood glucose levels or an improvement in insulin sensitivity, reduction in insulin levels or an enhancement of insulin secretion is beneficial. Compositions used in the therapy are also disclosed.
BACKGROUND OF THE INVENTION
Diabetes mellitus (or diabetes) is one of the most prevalent diseases in the world today. Diabetes patients have been divided into two classes, namely type I or insulin-dependent diabetes mellitus and type II or non-insulin dependent diabetes mellitus (NIDDM). NIDDM accounts for approximately 90% of all diabetics and is estimated to affect 12-14 million adults in the U.S. alone (6.6% of the population). NIDDM is characterized by both fasting hyperglycemia and exaggerated postprandial increases in plasma glucose levels. NIDDM is associated with a variety of long-term complications, including microvascular diseases such as retinopathy, nephropathy and neuropathy, and macrovascular diseases such as coronary heart disease. Numerous studies in animal models demonstrate a causal relationship between long term hyperglycemia and complications. Results from the Diabetes Control and Complications Trial (DCCT) and the Stockholm Prospective Study demonstrate this relationship for the first time in man by showing that insulin-dependent diabetics with tighter glycemic control are at substantially lower risk for the development and progression of these complications. Tighter control is also expected to benefit NIDDM patients.
Current therapies used to treat NIDDM patients entail both controlling lifestyle risk factors and pharmaceutical intervention. First-line therapy for NIDDM is typically a tightly-controlled regimen of diet and exercise since an overwhelming number of NIDDM patients are overweight or obese (67%) and since weight loss can improve insulin secretion, insulin sensitivity and lead to normoglycemia. Normalization of blood glucose occurs in less than 30% of these patients due to poor compliance and poor response. Patients with hyperglycemia not controlled by diet alone are subsequently treated with oral hypoglycemics or insulin. Until recently, the sulfonylureas were the only class of oral hypoglycemic agents available for NIDDM. Treatment with sulfonylureas leads to effective blood glucose lowering in only 70% of patients and only 40% after 10 years of therapy. Patients that fail to respond to diet and sulfonylureas are subsequently treated with daily insulin injections to gain adequate glycemic control.
Although the sulfonylureas represent a major therapy for NIDDM patients, four factors limit their overall success. First, as mentioned above, a large segment of the NIDDM population do not respond adequately to sulfonylurea therapy (i.e. primary failures) or become resistant (i.e. secondary failures). This is particularly true in NIDDM patients with advanced NIDDM since these patients have severely impaired insulin secretion. Second, sulfonylurea therapy is associated with an increased risk of severe hypoglycemic episodes. Third, chronic hyperinsulinemia has been associated with increased cardiovascular disease although this relationship is considered controversial and unproven. Last, sulfonylureas are associated with weight gain, which leads to worsening of peripheral insulin sensitivity and thereby can accelerate the progression of the disease.
Results from the U.K. Diabetes Prospective Study also showed that patients undergoing maximal therapy of a sulfonylurea, metformin, or a combination of the two, were unable to maintain normal fasting glycemia over the six year period of the study.
U.K. Prospective Diabetes Study 16
. Diabetes
, 44:1249-158 (1995). These results further illustrate the great need for alternative therapies.
Another drug therapy recently developed for NIDDM patients acts on the underlying mechanisms of insulin resistance and thereby lower glucose by enhancing insulin action at both peripheral and hepatic sites. Saltiel & Olefsky
Diabetes
45: 1661-1669 (1996). Accordingly, these agents are reported to increase insulin-dependent glucose disposal and to inhibit HGO. These agents are commonly referred to as “insulin sensitizers”.
One class of insulin sensitizers are compounds containing a thiazolidinedione. These compounds are reported to enhance insulin action without directly stimulating insulin secretion. Thiazolidinediones markedly decrease glucose levels in a variety of obese, insulin-resistant diabetic animal models including the KK-mouse, ob/ob mouse, Zucker Diabetic Fatty rat and db/db mouse. Similar effects are found in non-genetic diabetic animal models, including the fructose fed rat and high fat fed rat. Animal models characterized by severe hypoinsulinemia, e.g. the STZ rat, fail to respond to these agents unless treated with insulin. Thiazolidinediones are also reported to restore the ability of insulin to suppress HGO.
Although the molecular target of insulin sensitizers and more specifically thiazolidinedione analogs is unknown, several studies suggest that peroxisome proliferator-activated receptors (PPAR &ggr;s) may be the target and therefore that ligands to these receptors will be useful antihyperglycemic agents. Lehmann et al.
J. Biol. Chem
. 270: 12953-12956 (1995). PPAR &ggr;s are members of the steroid/thyroid hormone receptor superfamily of transcription factors. At least three PPAR &ggr;s exist, namely the &agr;, &bgr; and &ggr; receptors and thiazolidinediones have been identified as ligands that activate the &bgr; and &ggr; receptors. Binding occurs at a concentration achieved in vivo and some data suggests that there is a correlation between PPAR &ggr; binding affinity and in vivo activity. Wilson et al.
J. Med. Chem
. 39: 665-668 (1996).
PPAR &ggr;s exist as a heterodimer with the retinoic acid X receptor (RXR). A co-repressor protein has been postulated to maintain the receptor in an inactive state similar to other nuclear receptors. Binding of molecules to the complex, i.e. PPAR &ggr; ligands and/or RXR ligands may lead to dissociation of the co-repressor protein and activation of the receptor, which in turn is postulated to interact with specific DNA sequences, PPRE's, and to activate or repress gene transcription. Accordingly, RXR ligands are thought to enhance insulin sensitivity and therefore be useful as antidiabetics either alone or in combination with PPAR &ggr; agonists such as a thiazolidinedione. Heyman et al., WO 97/10819. In db/db mice, the combination of an RXR ligand and a PPAR &ggr; agonist reduces glucose levels more than either component alone.
Other classes of insulin sensitizers (i.e. non-thiazolidinediones) have been identified. For example, the insulin sensitizers SB 236636 and SB 219994 are 3-aryl-2-alkoxy propanoic acids. These compounds are reported to bind to human PPAR &ggr; with high affinity. SB 236636 is equipotent with thiazolidinedione BRL 49653 in stimulation of glucose transport in differentiated 3T3-L1 adipocytes and in glucose lowering activity in ob/ob mice. Young et al.
Diabetes
(1997). Relative to other thiazolidinediones, SB 236636 was shown to bind with higher affinity to crude extracts of Sf9 cells transfected with full length hPPAR &ggr; and rat adipocytes. This higher binding affinity correlated well with in vivo potency.
Some data suggests that chronic activation of PKC isoenzymes is involved in the generation of muscle insulin resistance and that insulin sensitizers may decrease the translocation of PKC isoenzymes from the cytosolic to particulate fractions in red skeletal muscle and therefore PKC activation. Schmitz-Peiffer et al.
Am. J. Physiol
. 273: E915-E921 (1997)
Angiotensin II antagonists and angiotensin converting enzyme inhibitors may be useful in enhancing insulin sensitivity based on potential interactions between angiotensin II and insulin signaling systems. Torlone et al. Diabetes Care 16: 1347-1355 (1993); Howard G. et al., Circulation 93: 1809-1817 (1996
Erion Mark D.
van Poelje Paul D.
Lewis Patrick
Metabasis Therapeutics, Inc.
Paul Hastings Janofsky & Walker
Wilson James O.
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