Antiobesity carbonic anhydrase inhibitors: a literature and patent review.
ABSTRACT Introduction: Obesity is ranked as one of the top 10 global health problems and the major concern deriving from it is the exposure of the population to a vast array of chronic pathologies such as cardiovascular and musculoskeletal disorders, type 2 diabetes, cancer, such as colon, breast and endometrial cancer, together with psychological disorders derived from this condition. The discovery that the clinically used anticonvulsants topiramate (TPM) and zonisamide (ZNS) induced weight loss in obese, epileptic patients, afforded the validation of the mitochondrial carbonic anhydrases (CAs, EC 126.96.36.199) VA and VB as targets for the development of antiobesity drugs. Areas covered: This review deals with the scientific and patent literature regarding obesity or obesity-related pathologies, being particularly focused on the use of carbonic anhydrase inhibitors (CAI) such as TPM and ZNS which inhibit the de novo lipogenesis. Expert opinion: There is an urgent need of new drugs for the treatment of obesity. The identification that the mitochondrial CAs are implicated in the de novo lipogenesis allowed to consider selective inhibitors of such enzymes as useful for the development of new antiobesity drugs. Actually TPM was approved 1 year ago for this therapy, whereas ZNS is also an effective such agent. These compounds are the lead molecules in this field and an intense research is on the way in order to develop new compounds based on the selective inhibition of mitochondrial CA isoforms.
- [Show abstract] [Hide abstract]
ABSTRACT: Molecules containing the sulfonamide group (R-SO2NH2) as well as its structurally related isosters, sulfamido (R-NH-SO2NH2) and sulfamato (R-O-SO2NH2), constitute the most important class of inhibitors acting on the metalloenzyme carbonic anhydrase (EC 188.8.131.52). Despite their presence in the literature, in general the reports lack of a clear and organic overview linking the main structural features of the clinically used inhibitors with the therapeutic aspects. The current review is intended to highlight the structural basis of the interactions of sulfonamide-like groups within the active site of the carbonic anhydrases and will summarize the clinical use of the most interesting molecules for the treatment of relevant pathologies, such as glaucoma, obesity, cancer and CNS-affecting diseases.Future medicinal chemistry 06/2014; 6(10):1149-1165. · 4.00 Impact Factor
- CNS Drugs 02/2015; · 4.38 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Sulfa drugs are well-known antibacterial agents containing N-substituted sulfonamide group on para position of aniline ring (NH2RSO2NHR(')). In this study 2,4-dichloro-1,3,5-triazine derivatives of sulfa drugs, sulfamerazine (1b), sulfaquinoxaline (2b), sulfadiazine (3b), sulfadimidine (4b), and sulfachloropyrazine (5b) (1a-5a) were synthesized and characterized. Their carbonic anhydrase inhibition activity was evaluated against bovine cytosolic carbonic anhydrase isozyme II (bCA II). For the sake of comparison the CA inhibition activity of the parent sulfa drugs (1b-5b) was also evaluated. A significant increase in CA inhibition activity of sulfa drugs was observed upon substitution with 2,4-dichloro-1,3,5-triazine moiety. Molecular docking studies were carried out to highlight binding site interactions. ADME properties were calculated to evaluate drug likeness of the compounds.BioMed Research International 09/2014; · 2.71 Impact Factor