title: New advances in models and strategies for developing anti-obesity drugs.
abstract: BACKGROUND
  Obesity is a worldwide pandemic. Obesity-related health and economic costs are staggering. Existing strategies to combat obesity through lifestyle improvements and medical intervention have had limited success. Pharmacotherapy, in combination with lifestyle modification, may play a vital role in reversing the disease burden. However, past and current weight-loss medications have had serious safety risks, notably cardiovascular and psychiatric events.
  
  
  METHODS
  The authors review the strategies for designing new anti-obesity drugs by describing those currently in development. They describe their target, mechanism of action and developmental or regulatory status. Furthermore, they discuss the problem of weight regain following weight loss, and its relevance to the long-term success of anti-obesity pharmacotherapy.
  
  
  CONCLUSIONS
  For weight management drugs to achieve the safety and efficacy required to be impactful, current studies are uncovering and characterizing new targets, including new signaling circuits and hormones regulating appetite and metabolism, and re-evaluating the role of pharmacotherapy in weight management. To avoid the safety failures of many past weight-loss drugs, the models and strategies covered in this article incorporate recent advances in knowledge and technology. We discuss the emergence of cGMP signaling as a potentially transformative target in weight management. Modulating cGMP signaling may represent an ideal goal for an anti-obesity pharmacotherapy, reflecting some of the major themes described in the present review: targeting pathways that are newly realized as relevant for weight management; promoting safety by re-purposing drugs that are safe, proven, and approved for clinical use; and having a synergistic effect on multiple, reinforcing pathways.
authors.affiliation: Thomas Jefferson University, Department of Pharmacology and Experimental Therapeutics, Philadelphia, PA 19107, USA.
authors.forename: Gilbert W
authors.initials: GW
authors.lastname: Kim
authors.forename: Jieru E
authors.initials: JE
authors.lastname: Lin
authors.forename: Erik S
authors.initials: ES
authors.lastname: Blomain
authors.forename: Scott A
authors.initials: SA
authors.lastname: Waldman
mesh_terms: D019440:Anti-Obesity Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001067:Appetite Depressants / Q000494:pharmacology* / Q000627:therapeutic use; D006152:Cyclic GMP / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D008019:Life Style; D008962:Models, Theoretical; D009765:Obesity / Q000188:drug therapy*; D015430:Weight Gain / Q000187:drug effects*; D015431:Weight Loss / Q000187:drug effects*
chemical_list: D019440:Anti-Obesity Agents; D001067:Appetite Depressants; D006152:Cyclic GMP