Anti-obesity carbonic anhydrase inhibitors: challenges and opportunities

Abstract

The mitochondrial isoforms VA/VB of metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) are involved in metabolic processes, such as de novo lipogenesis and fatty acid biosynthesis. We review the drug design landscape for obtaining CA VA/VB-selective/effective inhibitors, starting from the clinical observations that CA inhibitory drugs, such as the antiepileptics topiramate and zonisamide, or the diuretic acetazolamide induce a significant weight loss. The main approaches for designing such compounds consisted in drug repurposing of already known CA inhibitors (CAIs); screening of synthetic/natural products libraries both in the classical and virtual modes, and de novo drug design using the tail approach. A number of such studies allowed the identification of lead compounds diverse from sulphonamides, such as tropolones, phenols, polyphenols, flavones, glycosides, fludarabine, lenvatinib, rufinamide, etc., for which the binding mode to the enzyme is not always well understood. Classical drug design studies of sulphonamides, sulfamates and sulfamides afforded low nanomolar mitochondrial CA-selective inhibitors, but detailed antiobesity studies were poorly performed with most of them. A breakthrough in the field may be constituted by the design of hybrids incorporating CAIs and other antiobesity chemotypes.

Opposing effects of clozapine and brexpiprazole on β-aminoisobutyric acid: Pathophysiology of antipsychotics-induced weight gain

“…Based on these clinical findings, ABAT suppression by vigabatrin does not seem to be a promising target for reducing antipsychotic-induced weight gain and metabolic complications originating from hypothalamic AMPK signalling activation. On the other hand, mitochondrial carbonic topiramate and zonisamide have been reported to be effective against antipsychotic-induced weight gain 74 . Unfortunately, these two antiepileptic drugs are inappropriate for patients with epilepsy and comorbid psychotic symptoms and mood disorders 75 .…”

Mitochondrial carbonic anhydrase VA and VB: properties and roles in health and disease

“…Inhibition studies on CA VA and CA VB. Mitochondrial human CA VA is unique owing to its role in several biosynthetic reactions, and it has been shown that CA VA is a potential target for the design of anti-obesity agents (Supuran, 2022). Although it is extremely difficult to design CA isoform-specific inhibitors owing to the very high similarity of the active sites (Alterio et al, 2012;Pinard et al, 2015), it is important to design inhibitors with minimal affinity to other CAs to avoid non-specific effects.…”

Five-Membered Heterocyclic Sulfonamides as Carbonic Anhydrase Inhibitors

“…For these reasons, the different CA isoforms have emerged as attractive targets for therapeutic intervention and many efforts were made in the design of novel and effective carbonic anhydrase inhibitors (CAIs). To date, CA inhibition has been shown to have therapeutic potential in the treatment of a wide range of diseases, including edema, glaucoma, epilepsy, obesity, neuropathic pain, and cancer [ 16 , 17 , 18 , 19 , 20 ].…”