Antiobesity carbonic anhydrase inhibitors: A literature and patent review

ArticleinExpert Opinion on Therapeutic Patents 23(6) · April 2013with29 Reads
DOI: 10.1517/13543776.2013.790957 · Source: PubMed
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 4.2.1.1) 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.
    • "Indeed originally hCA inhibitors (hCAIs) were clinically used as diuretic [4], antiglaucoma [5], and antiepileptic [6][7][8][9], whereas their employment as antiobesity drugs [10,11] or in the management of hypoxic tumors [12][13][14]were only recently validated. Well known clinically used hCAIs are Acetazolamide AAZ, Methazolamide MZA, Ethoxzolamide EZA, Dorzolamide DZA, Brinzolamide BRZ, Benzolamide BZA, Topiramate TPM, Zonisamide ZNS, Sulpiride SLP and Indisulam IND are best known sulfonamide and its bio-isosters as antiepileptic drug (Figure 1) [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. However, because of the large number of hCA isoforms, there is a constant need to improve the inhibition and selectivity profile of the so far developed CAIs, in order to avoid side effects due to inhibition of isoforms not involved in a certain pathology [1][2][3]. "
    [Show abstract] [Hide abstract] ABSTRACT: Antiepileptic activity study considering the MES model and molecular docking studies were performed for a series of previously synthesized dioxoisoindolin benzene sulfonamide derivatives. The reported molecules were investigated as inhibitors of the zinc metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), specifically against the hCA I and II isoforms. To get a better insight of these molecules as potential inhibitors we specifically consider the hCA I (Ki values in the range 159 nM to >10000 nM) and hCAII (Ki values in range 1.7 nM to >10000 nM). The most potential molecule explored in the study was 3-(4,5,6,7-tetrachloro-1,3-dioxoisoindolin-2-yl)benzenesulfonamide (Ki=27.7 nM), 3-chloro-4-(4,5,6,7-tetrachloro-1,3-dioxoisoindolin-2-yl)benzenesulfonamide (Ki=4.9 nM) and 4-((4-nitro-1,3-dioxoisoindolin-2-yl)methyl)benzenesulfonamide (Ki=34 nM) respectively with obtained p-value <0.01 in the MES study and showed higher antepileptic activity than acetazolamide (AZM). Moreover a well defined docking score with RMSD value of 1.8 throws light on their effective binding to the active site of both 1AZM and 1ZFQ respectively.
    Full-text · Article · Jun 2016 · BioMed Research International
    • "Additionally, it has been proven that TPM also inhibits lipogenesis in adipocytes, similarly to other sulfonamide CA inhibitors [22]. On these grounds, this category of drugs has recently drawn attention as a promising new approach to treat obesity [3, 23]. The data of the present study are in line with those of the literature, confirming that a significant loss of body weight can occur within the first 6 months of treatment at TPM doses used to treat migraine patients, ranging most commonly between 100 and 200 mg/day. "
    [Show abstract] [Hide abstract] ABSTRACT: Purpose: To monitor weight regain after therapy discontinuation in patients with migraine experiencing weight loss during topiramate (TPM) treatment. Methods: Patients with migraine without aura were enrolled in this observational prospective study. Weight, body mass index (BMI), waist circumference, systolic and diastolic blood pressure, plasma levels of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, leptin, and ghrelin, and homeostatic model assessment of insulin resistance (HOMA-IR) were evaluated before starting TPM (T1), at 3 (T2) and 6 (T3) months of treatment and 6 months after withdrawal of TPM (T4). Weight loss/regain was considered as a change of </>5% of pre-TPM body weight. Results: A total of 241 patients were analyzed. Of these, 87 (36%) patients experienced weight loss on TPM medication. During TPM therapy significant reductions in mean values of weight (p<0.001), BMI (p<0.001), waist circumference (p<0.01), HOMA-IR (p<0.01), and leptin (p<0.01) were observed. After TPM discontinuation, all of these parameters showed a clear trend to increase at T4, achieving pre-TPM values in 27 patients. Among potential predictors, only HOMA-IR before starting TPM (parameter estimate=1.36, effect size=0.75; p=0.006) was significantly associated with weight regain after therapy discontinuation. Conclusions: Loss of body weight is a reversible effect, which at 6 months after TPM discontinuation shows a clear trend to return to baseline values. HOMA-IR is the only predictive factor of weight regain.
    Full-text · Article · Feb 2015
    • "Many clinically established drugs are CA inhibitors and are used to treat disorders such as glaucoma, acidic ulcers, mountain/sea sickness, and epilepsy [12]. Carbonic anhydrase is also an important drug target for treating obesity and many sulfonamide inhibitors have proved to be efficient antiobesity agents13141516. 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 low171819202122. Sulfonamides and their derivatives are well-known inhibitors of carbonic anhydrase [18, 23]. "
    [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.
    Full-text · Article · Sep 2014
Show more