New and Emerging Drug Molecules Against Obesity

Abstract

Obesity has become a growing pandemic of alarming proportions in the developed and developing countries over the last few decades. The most perturbing fact regarding obesity is the increased predisposition for coronary artery disease, congestive heart failure and sudden cardiac death. The modest efficacy of current anti-obesity agents such as orlistat and the increasing withdrawals of several anti-obesity agents such as sibutramine, rimonabant have led to huge gaps in the pharmacotherapy of obesity. Lorcaserin and Phentermine-topiramate combination (phen-top) are two drugs approved by US FDA in 2012. Lorcaserin, a 5HT2C agonist has moderate efficacy with an acceptable safety profile. Clinical trials with Phen-top have shown a reasonable efficacy but at the cost of risks such as teratogenicity and psychiatric disturbances. Cetilistat, a lipase inhibitor is claimed to have superior safety profile to orlistat and is in phase 3 clinical trials. Other promising anti-obesity molecules acting on the gut which are in clinical trials include exenatide and liraglutide. Drugs which act on the monoaminergic and opioid systems include bupropion-naltrexone and bupropion-zonisamide. Other novel first-in-class drugs which have been explored and have limited success in early clinical development include velneperit, tesofensine, and beloranib. Tesofensine is a triple monoamine re-uptake inhibitor, velneperit acts as a neuropeptide Y5 receptor antagonist and beloranib is a methionine amino peptidase 2 inhibitor. Novel targets such as histamine H3 receptor, VEGF, matrix-metalloproteinase, sirtuin receptors are also being investigated. This review is an attempt to describe the new and emerging molecules that are in clinical development for obesity.