Are carbonic anhydrase inhibitors suitable for obtaining antiobesity drugs?

Obesity is widespread disease both in the developed and developing world, which currently affects over 300 million individuals worldwide and is associated with premature mortality and chronic morbidity. Although diet, physical activity and behavioral modifications should theoretically help in controlling this condition, very often these strategies are insufficient to normalize the multiple risks associated with this condition. Thus, pharmacological interventions for the treatment of this disease are essential. Paradoxically, the currently available drugs for the treatment of obesity are very few, their mechanism of action is hardly understood and their side effects are generally quite serious. Therefore, novel effective anti-obesity drugs possessing different mechanisms of action are needed. In this review we describe in detail a possible new approach for the treatment and prophylaxis of this disease based on the inhibition of Carbonic Anhydrases (CAs, EC 4.2.1.1), enzymes involved in several steps of de novo lipogenesis. In particular, we summarize here a series of kinetic and structural studies recently reported on Topiramate (TPM) and Zonisamide (ZNS), two antiepileptic drugs showing strong CA inhibitory properties, that were shown to induce persistent weight loss in obese patients. On the basis of the reviewed studies we suggest that the use of TPM and ZNS as lead molecules for the design of CA inhibitors targeting isozymes involved in lipogenesis could represent the beginning of a very promising approach for the treatment of obesity.