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Preclinical and Clinical Anti-obesity and Anti-diabetes Targets

Anti-obesity

Obesity has become a global epidemic. 1.1 billion people worldwide are estimated to be over their ideal weight, i.e., with a body mass index (BMI) above 24.9 kg m-2 (Melnikova, I, Wages, D Nature Reviews Drug Discovery 5:369-370, 200). In the United States, 127 million people or 65% of adults, and an increasing number of children and adolescents are considered overweight (BMI > 24.9 kg m-2) or obese (BMI > 30 kg m-2) (Melnikova, I, Wages, D Nature Reviews Drug Discovery 5:369-370, 200). Obesity is associated with and often considered to precipitate other conditions such as type 2 diabetes, hypertension, cardiovascular disease, stroke, certain types of cancer, gout, sleep apnea, etc.

Obesity is a condition in which energy intake exceeds energy expenditure. Diet and exercise are the preferred weight controlling approaches but usually not effective for long-term efficacy due to the lack of discipline by the individual and the body's ability to adjust its energy efficiency (Leibel, RL, Rosenbaum M, Hirsch J New England J Med 332:621-8, 1995). Pharmacological intervention approaches have attempted to take advantage of both sides of the energy equation, i.e., limiting energy intake and increasing energy expenditure by regulating metabolism.

Currently, only sibutramine and orlistat have been approved for anti-obesity indication. Rimonabant could become the third anti-obesity drug with a FDA approvable letter issued in February, 2006. All of them aim at controlling energy intake. Sibutramine is a dual serotonin and norepinephrine reuptake inhibitor that suppresses appetite (Nisoli E, Carruba MO Drug Saf 26:1027-48, 2003). Orlistat is a lipase inhibitor that blocks fat absorption (Nelson RH, Miles JM Expert Opinion Pharmacotherapy 6:2483-91, 2005). Rimonabant is an appetite suppressant through its antagonism on the cannabinoid type I (CB1) receptor (Pi-Sunyer, FX et al. J Am Med Assoc 295:761-765, 2006). Although sibutramine and orlistat received limited marketing success relative to the potential anti-obesity market because of their respective side effects, these drugs do demonstrate that limiting energy intake either through appetite suppression or blocking nutrient absorption could achieve certain degree of clinical efficacy in weight control. On the other hand, no drug has been approved to date for anti-obesity by metabolic modulation and thus, the concept of using a "metabolic agent" (vs. an appetite suppressant( as an anti-obesity drug remains at the exploratory, pre-clinical stage.

Listed below are compounds that have been investigated and reported in literature as potential novel anti-obesity drugs. The compounds are classified by their anti-obesity mechanisms or by structures or known indications if their anti-obesity mechanisms are yet to be elucidated. The reduction of body weight and body fat composition has therapeutic effects on the control of type 2 diabetes. Thus, anti-obesity drugs could potentially be anti-diabetes drugs through, e.g., the indirect improvement of insulin sensitivity. Some of these compounds may also have direct therapeutic effects on both body weight and blood glucose.

Appetite Suppression

Nutrient Blockers

Metabolic Modulators

Anti-type 2 Diabetes

Like obesity, type 2 diabetes has also become a worldwide epidemic, partially due to the increased incidence of obesity. It is estimated that 200 million people have diabetes worldwide, 90% of which are type 2 (Int'l Diabetes Fed. 2004 http://www.idf.org/home). Diabetes is defined as a condition of fasting and postprandial hyperglycemia. Insulin resistance and β-cell dysfunction are believed to be the culprits of type 2 diabetes and it requires both to manifest hyperglycemia. Pharmacotherapy of either can control the blood glucose level.

The ultimate consequence of chronic hyperglycemia is diabetic complications, notably macrovascular and microvascular diseases (Brownlee M Diabetes 54:1615-25, 2005). No drugs have been approved for diabetic complications. However, it has been unequivocally demonstrated that there is a linear relationship between controlling blood glucose level and delaying the onset and slowing the progression of nephropathy, neuropathy and retinopathy (The Diabetes Control and Complications Trial Research Group N Engl J Med 329:977- 86, 1993; UK Prospective Diabetes Study (UKPDS) Group Lancet 352:837-53, 1998). Five classes of drugs have been approved to control blood glucose: sulfonylurea insulin secretagogues, metformin, thiazolidinedione (TZD) insulin sensitizers, a-glucosidase inhibitor (acarbose), and exenatide, an incretin mimetic (Krentz AJ, Bailey CJ Drugs 65:385-411, 2005; Cheng AY, Fantus IG Can Med Assoc J 172:213-32, 2006; Iltz JL, et al. Clin Ther 28:652-65, 2006). Listed below are compounds and approaches that have been reported as potential anti-diabetes agents.

Targeting ß-cells

Targeting metabolism

Ciglitazone was initially discovered as an antihyperlipidemic agent (Kawamatsu Y et al. Arzneim-Forsch/Drug Res 30:454-9, 1980; ibid 30:585-9, 1980; ibid 751-8, 1980). It was the first thiazolindinedione (TZD) structure that received extensive studies as an anti-diabetes agent (Sohda T et al. Chem Pharm Bull 30:3580-600, 1982; Chang A et al. Diabetes 32:830-8, 1983; ibid 32:839-45, 1983; Fujita T et al. Diabetes 32:804-10, 1983). Although ciglitazone failed to become a clinical candidate, its novel mechanism in improving insulin sensitivity raised an intense interest in this class of compounds and many TZD structures were synthesized (Saltiel AR, Horikoshi H Current Opinion in Endocrinol and Diabetes 2:341-7, 1995; Stevenson RW et al. The Diabetes Annual 9:175-91, 1995). Several of them became clinical candidates. Troglitazone (Horikoshi H, Hashimoto T, Fujiwara T Prog Drug Res 54:193-212, 2000) was approved in the U.S. and UK in 1997 with indications for diabetes. It was withdrawn from the market place in the UK a few weeks after launching and in the U.S. in 2000 due to hepatotoxicity. Rosiglitazone (Wagstaff AJ Goa KL Treatments in Endocrinol 1:411-1, 2002) and pioglitazone (Vasudevan AR Balasubramanvam A Diabetes Tech Therap 6:850-63, 2004) were launched in the U.S. in 1999 and in Europe in 2000.

TZDs are peroxisome proliferators-activated receptor gamma (PPARr) agonists (Staels B Fruchart J-C Diabetes 54:2460-70, 2005). These compounds enhance the proliferation of of preadipocytes into adipocytes to facilitate free fatty acid uptake and triglyceride storage in subcutaneous adipose depots This reduction of plasma free fatty acid improves systemic insulin sensitivity which increases glucose uptake in liver and skeletal muscle, reduces gluconeogenesis and lowers blood glucose.

Clinically, in addition to decrease blood glucose and HbA1c levels, pioglitzone and rosiglitazone also decrease plasma insulin, an indication of improved insulin sensitivity in concomitant with the lowering of blood glucose, and triglyceride concentrations. These drugs pose minimum hypoglycemic risk. However, they cause fluid retention and increase of body weight which are not desirable for subjects with diabetes. Ciglitazone was found to promote ß-cell regranulation with improved insulin synthesis and storage in ob/ob and db/db mice (Diani AR et al. Diabetologia 27:225-34, 1987). This has been confirmed in humans with pioglitazone and rosiglitazone (Leiter LA Diabetic Med 22:963-72, 2005; Kim SH et al. Diabetes 54:2447-52, 2005 ).

 

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