Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-01-22
2004-03-30
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S314000, C546S169000, C546S170000
Reexamination Certificate
active
06713489
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to compounds that inhibit the secretion of apolipoprotein B, and to methods of treating and/or preventing atherosclerosis, obesity, diabetes, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, hypoalphalipoproteinemia, pancreatitis, myocardial infarction, stroke, restenosis, or Syndrome X. This invention also relates to methods of reducing the secretion of apolipoprotein B and/or inhibiting microsomal triglyceride transfer protein.
BACKGROUND OF THE INVENTION
Microsomal triglyceride transfer protein (MTP) catalyzes the transport of triglycerides, cholesteryl esters and phospholipids, and MTP is involved in the assembly of lipoproteins that contain apolipoprotein B (apo B). Examples of lipoproteins that contain apo B include lipoprotein (a) [Lp(a)], low density lipoprotein (LDL), and very low density lipoprotein (VLDL), which is a precursor to LDL. Compounds that contain apo B are known to contribute to the formation of atherosclerotic lesions.
A noteworthy disease in which MTP plays a direct role is abetalipoproteinemia. This disease is characterized by the virtual absence of plasma lipoproteins containing apo B. For example, plasma triglyceride levels may be as low as a few mg/dl, and plasma cholesterol levels are often only 20-45 mg/dl. Interestingly, autopsies of patients having abetalipoproteinemia reveal that these patients are free of atherosclerosis. Recently, it has been discovered that this disease is caused by a defect in the MTP gene.
Compounds that inhibit MTP and/or apo B secretion are useful in the treatment and/or prevention of atherosclerosis, obesity, diabetes, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, hypoalphalipoproteinemia, pancreatitis, myocardial infarction, stroke, restenosis, and Syndrome X. The inhibition of MTP and/or inhibition of apo B secretion typically results in the lowering of plasma concentrations of compounds that contain apo B.
In the treatment of obesity, one of the primary therapeutic goals is the suppression of caloric intake through appetite control. In order to effect practical appetite control, many therapeutic regimens have evolved such as the use of methodologies targeting certain central and peripheral biopsychological systems, including the use of periphery drugs that blunt either positive afferent information or intensify inhibitory afferent information. As such, these drugs may stimulate chemoreceptor activity in the gut or modulate gastrointestinal functioning via a network of neurotransmitters located in the enteric plexus. Other drugs may serve to mimic or perform surrogative functions for appetite-regulating factors in the blood, alter oxidative hepatic metabolism, adjust metabolic satiety signals or modify amino acid profiles. Finally, drugs may affect steroid levels reflecting energy metabolism, which, in turn, influences neuronal function, for example the corticosteroidal upregulation of adrenoreceptors in the paraventricular nucleus.
Generally, drugs affecting digestion or lipid absorption can be expected to alter the timing and pattern of nutritional information reaching the brain. Within the brain, drugs are believed to alter appetite via a number of neurotransmitter and neuromodulator systems at a variety of specific sites; however, the influence of central neurochemical activity on the expression of appetite is complex and involves numerous interactions between disparate loci and receptors resulting in shifts in the magnitude, direction and quality of feeding behavior.
While many cogent theories have been advanced based on data and direct observation, the physiology of the control of food intake is not well understood and interest in the development of safe and efficacious appetite controlling drugs remains high. See, for example, Kissilev et al.,
Ann. Rev. Nutr.,
2:371-418 (1981) and Russek, et al.,
Appetite,
2:137-143 (1981).
Conventional therapeutic approaches to the treatment of obesity have traditionally focused on the regulation of energy intake. Unfortunately, there is now a growing awareness that, while moderation of caloric intake is initially effective in reducing body weight, such regimens are not particularly effective over the long-term. In response, alternative strategies requiring less rigorous observation of caloric consumption have been developed, including the use of agents that alter the absorption of dietary fat from the gastrointestinal tract.
The gastrointestinal digestion and absorption of ingested lipids consists of several steps. Following dispersion of bulk fat into finely emulsified droplets in the stomach, fatty acid esters are hydrolyzed enzymatically, partially by the action of gastric lipase in the stomach, but predominantly by pancreatic lipase in the upper small intestine. In recent years, studies concerning certain inhibitors of pancreatic lipase, orlistat for example, have indicated that treatment with such inhibitors may hold promise in the treatment of obesity. However, in view of the complexity of the genetic component of obesity and the psychologic factors involved in maintaining lifestyle habits, the long-term efficacy of such drugs in managing body weight and decreasing obesity-related medical complications is unknown. Thus, the identification of alternative therapeutic regimens remains desirable.
The treatment of obesity is also an important therapeutic goal for the reduction of secondary disorders, including diabetes, peripheral vascular disease, hypertension, and the like. Dietary lipids represent a significant source of calories and therapeutic approaches that reduce the absorption of lipids may include, for example, reduction in the intake, digestion or absorption of lipids. In order for dietary lipids to be absorbed, they must initially be converted by hydrolysis into monoacylglycerides and free fatty acids. The inhibition of this hydrolytic cleavage of triglycerides by lipase inhibitors results in decreased absorption of monoacylglycerides and free fatty acids leading to the decreased consumption of fat with concomitant reduction or prevention of the abnormalities related thereto.
In one aspect, the present invention provides a method of treating or preventing obesity in a patient in need thereof using a compound of the present invention, or a combination of a compound of the present invention with one or more additional anti-obesity agents.
The present invention also provides a method of reducing intestinal fat absorption in a patient in need thereof using a compound of the present invention, or a combination of a compound of the present invention with one or more additional anti-obesity agents.
The present invention also provides a method for reducing food intake in a patient in need thereof using a compound of the present invention, or a combination of a compound of the present invention with one or more additional anti-obesity agents.
The glycoprotein apolipoprotein (a), [apo(a)], is synthesized and secreted by hepatic cells, and in humans, circulates largely in association with LDL in the form of a hybrid lipoprotein referred to as LP(a). The association between apo(a) and the major protein moiety of LDL, namely apolipoprotein B100 (apo B100), is mediated through covalent linkage of a single unpaired cysteine residue in apo(a) to a complimentary unpaired cysteine residue in the extreme carboxyl terminus of apo B100.
Interest in the biology of this lipoprotein species is driven by the observation that an elevated plasma level of Lp(a) in humans is associated with an increased risk for atherosclerotic heart and vascular disease. The lowering of Lp(a) levels, however, has proven problematic since various conventional methods that are effective in reducing levels of LDL are not as efficacious or consistent in lowering levels of Lp(a). For example, it has been reported that neomycin, alone or in combination with niacin, is effective in reducing Lp(a) levels when administered over a period of several weeks to years. See Spinler, et
Ruggeri Roger
Wilson Douglas
Benson Gregg C.
Huang Evelyn Mei
Pfizer Inc
Richardson Peter C.
Samuels Lisa A.
LandOfFree
7-[(4′-trifluoromethyl-biphenyl-2-carbonyl)amino&... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 7-[(4′-trifluoromethyl-biphenyl-2-carbonyl)amino&..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 7-[(4′-trifluoromethyl-biphenyl-2-carbonyl)amino&... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3208643