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Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Prakash et al. (2007) have systematically investigated the disposition of ezlopitant in humans. After oral administration of 14C-ezlopitant to healthy male volunteers, the total recovery of administered radioactive dose is 82.8%, with 32.0% in the urine and 50.8% in the feces. The major disposition pathway of ezlopitant in humans is the oxidation of the isopropyl side chain to form the w-hydroxy and w-1-hydroxy (M16) metabolites. M16 and ω,ω-1-dihydroxy (1,2-dihydroxy, M12) are identified as the major circulating metabolites, accounting for 64.6% and 15.4% of total circulating radioactivity, respectively (Prakash et al. 2007). In feces, the major metabolite M14 is the propionic acid metabolite formed by further oxidation of the ω-hydroxy metabolite. The urinary metabolites are the result of cleaved metabolites caused by oxidative dealkylation of the 2-benzhydryl-1-aza-bicyclo[2.2.2]oct-3-yl moiety. The metabolites (M1A, M1B, and M4) are as benzyl amine derivatives, accounting for ~34% of the total radioactivity in urine. The other metabolites are formed by O-demethylation, dehydrogenation of the isopropyl group, and oxidation on the quinuclidine moiety (Prakash et al. 2007).
Synthesis of novel benzenesulfamide derivatives with inhibitory activity against human cytosolic carbonic anhydrase I and II and Vibrio cholerae α- and β-class enzymes
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Silvia Bua, Emanuela Berrino, Sonia Del Prete, Vallabhaneni S. Murthy, Vijayaparthasarathi Vijayakumar, Yasinalli Tamboli, Clemente Capasso, Elisabetta Cerbai, Alessandro Mugelli, Fabrizio Carta, Claudiu T. Supuran
In this work, we reported the investigation of benzenesulfamide derivatives (–NH-SO2NH2) as an alternative zinc binding class of inhibitors to the primary aromatic sulfonamides in the design of new potential bacterial CAIs17. The “tail approach”, the method that consists in varying the terminal portions of the molecule to selectively enhance the inhibition of the target isoform(s), was applied to the phenyl sulfamide scaffold. All compounds were synthesised by a convenient and efficient method and were screened for in vitro inhibition against cytosolic isoenzymes hCA I, II, VchCAα and VchCAβ by using a stopped-flow CO2 hydrase assay method. The obtained results suggest that the benzhydryl piperazine moiety appended to benzene-sulfamide functionalities are not favourable for the interaction with Vibrio cholerae CA isoforms. Conversely, the same moiety is slightly more favourable for the inhibition of hCA I, as demonstrated by compounds 6f, 6m, 6p, and 6d that showed interesting activities against this isoform, with a nanomolar inhibition constant (KIs = 43.1, 47.8, 49.1, and 58.1 nM, respectively), being thus more potent than AAZ (as standard inhibitor).
Antihistamines, phenothiazine-based antipsychotics, and tricyclic antidepressants potently activate pharmacologically relevant human carbonic anhydrase isoforms II and VII
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Francesco Fiorentino, Alessio Nocentini, Dante Rotili, Claudiu T. Supuran, Antonello Mai
The cytosolic hCA VII was efficiently activated by the compounds investigated in the study, and all of them possessed an improved activation profile compared to 1, with a wide range of derivatives being active in the low micromolar range. Specifically, half of the assayed compounds exhibited a KA value lower than 5 µM. These include: (i) the benzhydryl derivatives 2 and 3; (ii) the phenothiazine-based compounds 7, 10, 11, and 12; (iii) the TCAs 13, 14, and 17. Among the tested molecules, the most promising hCA VII activator was desipramine 14 (KA = 1.6 µM), the mono desmethyl analogue of 13, which could still activate hCA VII, albeit almost 2-fold less efficiently. The same structure-activity relationship (SAR) was observed for TCAs 15 and 16, with the mono desmethyl derivative being >2-fold more potent than its parent compound 15. Conversely, the phenothiazines bearing a 1,3-diaminopropane chain (7 and 8) followed the opposite trend, with 7 being ∼3.5-fold more potent than the mono desmethyl analogue 8. In the case of the phenothiazine-based 1,2-diaminopropane compounds 5 and 6, removal of both N-methyl groups led to a 3-fold decrease in CA VII activation potency. Interestingly, compound 2, which was inactive towards all other isoforms, was a good hCA VII activator (KA = 4.7 µM). Similarly, TCAs 17 and 18, which were only weakly potent towards hCA II, could both activate hCA VII with KA values of 4.9 and 9.2 µM, respectively.
Antibacterial carbonic anhydrase inhibitors: an update on the recent literature
Published in Expert Opinion on Therapeutic Patents, 2020
Claudiu T. Supuran, Clemente Capasso
The sulfonamide and sulfamate inhibition profile for the α-CA (VchCAα) led to the detection of a large number of low nanomolar inhibitors, among which MZA, AAZ, EZA, DZA, BRZ, BZA, and IND (KIs in the range 0.69–8.1 nM) [115]. Some sulfonamide inhibitors were modified to overcome the scarcity of selective inhibition profiles associated with CAIs belonging to the classical zinc binders. Thirteen novel sulfonamide derivatives incorporating the quinazoline scaffold were thus tested as VchCAα inhibitors [116]. Nine compounds were highly active as nanomolar inhibitors of the pathogenic enzyme VchCA. The best VchCAα inhibitor had a KI of 2.7 nM. Many of these developed compounds showed high selectivity for inhibition of the bacterial over the mammalian CA isoforms, with one compound possessing selectivity ratios as high as 97.9 against hCA I and 9.7 against hCA II [116]. Other benzenesulfonamides incorporating water solubilizing moieties, such as N-alpha-acetyl-l-lysine or GABA scaffolds were highly effective, nanomolar inhibitors of VchCAα [117]. A series of acyl selenoureido benzensulfonamides also showed strong inhibitory action against VchCAα but not for the VchCAβ, and had an excellent selectivity over the off-target isoforms hCA I and II [118]. Sulfonamides incorporating imidazole moieties were low nanomolar VchCAα inhibitors, whereas their inhibition of the human cytosolic isoforms CA I and II was in the micromolar range or higher [119]. Selenides bearing benzenesulfonamide moieties were excellent and selective inhibitors of VchCAα over the off-target isoforms hCA I and II [120]. Sulfamides incorporating ortho-, meta-, and para-benzenesulfamide moieties prepared by using the ‘tail approach’ incorporating benzhydryl piperazine tails showed a rather good efficacy against hCA I and VchCAα, with several compounds showing KIs < 100 nM [121]. Click-tailed benzenesulfonamides with diverse spacers between benzenesulfonamide and triazole moiety were also investigated, and some excellent VchCAα inhibitors were detected, with KIs between 0.72 and 22.6 nM [122].