aod-9604 and Obesity

A number of anti-obesity drugs are currently undergoing clinical development. These include: (i) centrally-acting drugs, such as the noradrenergic and dopaminergic reuptake inhibitor radafaxine, the endocannabinoid antagonist rimonabant, the selective serotonin 5-HT2c agonist APD-356, and oleoyl-estrone; (ii) drugs that target peripheral episodic satiety signals, such as glucagon-like peptide-1 (exenatide, exenatide-LAR and liraglutide), peptide YY (intranasal PYY3-36 and AC-162325) and amylin (pramlintide); (iii) drugs that block fat absorption, such as the novel lipase inhibitors cetilistat and GT-389255; and (iv) a human growth hormone fragment (AOD-9604) that increases adipose tissue breakdown. Of these, only rimonabant has got as far as completing phase III clinical trials. This review will provide an overview of the most prominent drugs currently undergoing clinical development as potential anti-obesity therapies.

Topics: Amyloid; Animals; Anti-Obesity Agents; Appetite Depressants; Energy Metabolism; Glucagon-Like Peptide 1; Humans; Islet Amyloid Polypeptide; Obesity; Peptide Fragments; Peptide YY; Receptor, Cannabinoid, CB1; Selective Serotonin Reuptake Inhibitors; Somatostatin

Metabolic is developing AOD-9604 for the potential treatment of obesity. By February 2002, phase IIa trials were underway.

Topics: Animals; Anti-Obesity Agents; Clinical Trials, Phase II as Topic; Humans; Obesity; Peptide Fragments; Somatostatin; Structure-Activity Relationship

Both human GH (hGH) and a lipolytic fragment (AOD9604) synthesized from its C-terminus are capable of inducing weight loss and increasing lipolytic sensitivity following long-term treatment in mice. One mechanism by which this may occur is through an interaction with the beta-adrenergic pathway, particularly with the beta(3)-adrenergic receptors (beta(3)-AR). Here we describe how hGH and AOD9604 can reduce body weight and body fat in obese mice following 14 d of chronic ip administration. These results correlate with increases in the level of expression of beta(3)-AR RNA, the major lipolytic receptor found in fat cells. Importantly, both hGH and AOD9604 are capable of increasing the repressed levels of beta(3)-AR RNA in obese mice to levels comparable with those in lean mice. The importance of beta(3)-AR was verified when long-term treatment with hGH and AOD9604 in beta(3)-AR knock-out mice failed to produce the change in body weight and increase in lipolysis that was observed in wild-type control mice. However, in an acute experiment, AOD9604 was capable of increasing energy expenditure and fat oxidation in the beta(3)-AR knock-out mice. In conclusion, this study demonstrates that the lipolytic actions of both hGH and AOD9604 are not mediated directly through the beta(3)-AR although both compounds increase beta(3)-AR expression, which may subsequently contribute to enhanced lipolytic sensitivity.

Topics: Adipose Tissue; Animals; Body Weight; Energy Metabolism; Human Growth Hormone; Humans; Lipid Metabolism; Lipolysis; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Oxidation-Reduction; Peptide Fragments; Receptors, Adrenergic, beta-3; Reference Values; RNA, Messenger; Somatostatin; Time Factors