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.

Keywords: Carbonic anhydrase; de novo lipogenesis; fatty acid biosynthesis; mitochondria; natural products; obesity; phenols; sulphonamides; topiramate; zonisamide.

Figure 1.

Role of mitochondrial and cytosolic CA isoforms in fatty acid biosynthesis: the transfer of acetyl groups from the mitochondrion to the cytosol (in the form of citrate) is required for the provision of substrate for de novo lipogenesis via malonyl-coenzyme A as key intermediate. Steps involving bicarbonate, both for the reaction catalysed by pyruvate carboxylase (PC) and acetyl-coenzyme A carboxylase (ACC) require the presence of CA isozymes: CA VA/VB in the mitochondrion and CA II in the cytosol.

Figure 2.

Sulphonamide/sulfamate CAIs in clinical use: acetazolamide (AAZ), zonisamide (ZNS) and topiramate (TPM).

Figure 3.

(A) hCA II complexed with superimposed topiramate (PDB 3HKU) in green, and zonisamide (PDB not deposited, available from the authors⁵²) in magenta. The Zn(II) is shown as a grey sphere that is bound to the protein ligands His94, His96 and His119. The hydrophobic half of the active site is coloured in red, the hydrophilic one in blue. His64, the proton shuttle residue, in green. Active site ribbon view of hCA II in adduct with B) TPM and C) ZNS. H-bonds are represented as black dashed lines. Active site ribbon view of hCA II in adduct with B) topiramate and C) zonisamide. H-bonds are represented as black dashed lines.

Figure 4.

Phenol and NP based phenols screened as hCA VA/VB inhibitors.

Figure 5.

NPs screened as hCA VA/VB inhibitors.

Figure 6.

hCA VA inhibitors 34–38 identified by VS techniques, and acipimox 39, identified by classical screening procedures.

Figure 7.

Sulfamides 45 and sulfamates 46–48 reported as hCA VA/VB inhibitors.

Figure 8.

Aromatic/heterocyclic sufonamides 49 and 50 incorporating 10-camphorsulfonyl tails. In derivatives 49, n = 0, 1 and 2. Triazole-sulphonamides 51 incorporate X, Y Z groups of the type H, F, Me, OMe, CF₃, SO₂NH₂.

Figure 9.

Chemical structures of Semaglutide (A), and Tirzepatide (B), recently approved anti-obesity agents.