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.

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

“…As the biomarker for obesity, NPY is a major mediator in promoting energy storage [104], which regulates food intake, fat deposition and metabolism via various G-proteincoupled NPY receptors including NPY receptor subtype 1, 2, and 5 [105,106]. For example, the NPY receptor sub-type 5 antagonist, Velneperit, has been identified in clinical tests as a potential anti-obesity drug [107,108]. It has been reported that injection of NPY into the PVN repeatedly led to sustained hyperphagia, body weight gain and fat mass accumulation [109,110].…”

Triple Reuptake Inhibitors as Potential Next-Generation Antidepressants: A New Hope?

“…The compound proved to be efficacious in weight loss. Sibutramine, was approved by the US FDA to treat obesity but was later withdrawn from market owing to its cardiovascular side effects [163]. Antiobesity effect of another TRI, DOV 21,947 has also been demonstrated in both preclinical and clinical studies [164,165].…”

Future management of human obesity: understanding the meaning of genetic susceptibility

“…However, appetite regulation is such a central process with links to and from many other systems (ANS, mood, etc) that it makes specific targeting without undesirable side effects potentially very difficult, as can been seen in the history of drug development in this area. 40 Recent interest in the melanocortin-4 receptor as a potentially targetable component of the NBH appears to be an illustration of continuing problems of this nature. Antagonist compounds to melanocortin-4 receptor are being developed for targeting depression and anxiety, 108 while agonists are being developed to target obesity.…”

“…109 This is reminiscent of the history of Rimonabant, a drug developed to target obesity though antagonism of cannabinoid receptors in satiety pathways but which was withdrawn due to side effects on depression. 40 An improved understanding of the properties of the appetite-regulating system as a control system could affect strategies for targeting. If, for example, the system is strongly hierarchical with lateral connections to other systems such as the ANS mainly at high levels in the hierarchy, that could be quite different in its implications from a more distributed network-like structure with many lateral connections.…”

“…11 There is almost no other area in drug development that is replete with as many failures and withdrawals as seen in obesity. 40 Current novel obesity agents include a 5HT2c receptor agonist (Lorcaserin), a combination of phentermine and extendedrelease topiramate (Qysmia), both of which have modest treatment effects and side effects of concern to regulatory agencies 41 and a peripherally acting drug (Beloranib, a methionine aminopeptidase inhibitor) currently in Phase III trials, so far without major side effects. 42 Of those three, only Beloranib offers a prospect of broad usage, but to date, results of treatment have only been reported out to 12 weeks.…”