Antiobesity carbonic anhydrase inhibitors: A literature and patent review
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 18.104.22.168) VA and VB as targets for the development of antiobesity drugs.
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.
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.
- SourceAvailable from: Mariya Al-Rashida
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- "Many clinically established drugs are CA inhibitors and are used to treat disorders such as glaucoma, acidic ulcers, mountain/sea sickness, and epilepsy . Carbonic anhydrase is also an important drug target for treating obesity and many sulfonamide inhibitors have proved to be efficient antiobesity agents    . The transmembrane isozymes CA IX and CA XII have been found to be overexpressed in hypoxic tumors (having acidic environment) whereas their distribution in normal cells remains low      . "
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; 2014. DOI:10.1155/2014/162928 · 2.71 Impact Factor
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ABSTRACT: We report here a series of 2-thiophene-sulfonamides incorporating 1-substituted aryl-1,2,3-triazolyl moieties, prepared by click chemistry from 5-ethynylthiophene-2-sulfonamide and substituted aryl azides. The new sulfonamides were investigated as inhibitors of the zinc metalloenzyme CA (EC 22.214.171.124), and more specifically against the human (h) cytosolic isoforms hCA I and II and the transmembrane, tumor-associated ones hCA IX and XII: The new compounds were medium-weak hCA I inhibitors (KIs in the range of 224-7544nM), but were compactly, highly effective, low nanomolar hCA II inhibitors (KIs of 2.2-7.7nM). The tumor-associated hCA IX was inhibited with KIs ranging between 5.4 and 811nM, whereas hCA XII with inhibition constants in the range of 3.4-239nM. The X-ray crystal structure of the adducts of two such compounds bound to hCA II (one incorporating 1-naphthyl, the other one 3-cyanophenyl moieties) evidenced the reasons of the high affinity for hCA II. Highly favorable, predominantly hydrophobic interactions between the sulfonamide scaffold and the hCA II active site were responsible for the binding, in addition to the coordination of the sulfamoyl moiety to the zinc ion. The tails of the two inhibitors adopted very diverse orientations when bound to the active site, with the naphthyltriazolyl moiety orientated towards the hydrophobic half of the active site, and the 3-cyanophenyl one pointing towards the hydrophilic half. These data may be used for the structure-based drug design of even more effective hCA II inhibitors, with potential use as antiglaucoma agents or as diuretics.Bioorganic & medicinal chemistry 06/2013; 21(17). DOI:10.1016/j.bmc.2013.06.041 · 2.79 Impact Factor
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ABSTRACT: 4-Amino-N-(4-sulfamoylphenyl)benzamide was synthesized by reduction of 4-nitro-N-(4-sulfamoylphenyl)benzamide and used to synthesize novel acridine sulfonamide compounds, by a coupling reaction with cyclic-1,3-diketones and aromatic aldehydes. The new compounds were investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 126.96.36.199), and more precisely the cytosolic isoforms hCA I, II and VII. hCA I was inhibited in the micromolar range by the new compounds (KIs of 0.16-9.64μM) whereas hCA II and VII showed higher affinity for these compounds, with KIs in the range of 15-96nM for hCA II, and of 4-498nM for hCA VII. The structure-activity relationships for the inhibition of these isoforms with the acridine-sulfonamides reported here were also elucidated.Bioorganic & medicinal chemistry 07/2013; 21(18). DOI:10.1016/j.bmc.2013.07.014 · 2.79 Impact Factor