| Reference | [1]. Francis, J. and Spinks, A., 1950.<br />
Antibacterial action and metabolism of five sulphones.<br />
British journal of pharmacology and chemotherapy, 5(4), p.565.<br />
<br />
[2]. Uetrecht, J., 1989.<br />
Review of Pharmacology and Theraputic Use.<br />
Clin. Dermatol, 7, pp.111-120.<br />
<br />
[3]. Reszka, K.J., McGraw, D.W. and Britigan, B.E., 2009.<br />
Peroxidative metabolism of β2-agonists salbutamol and fenoterol and their analogues.<br />
Abstract Abstract: Phenolic β2-adrenoreceptor agonists salbutamol, fenoterol, and terbutaline relax smooth muscle cells that relieve acute airway bronchospasm associated with asthma. Why their use sometimes fails to relieve bronchospasm and why the drugs appear to be less effective in patients with severe asthma exacerbations remains unclear. We show that in the presence of hydrogen peroxide, both myeloperoxidase, secreted by activated neutrophils present in inflamed airways, and lactoperoxidase, which is naturally present in the respiratory system, catalyze oxidation of these β2-agonists. Azide, cyanide, thiocyanate, ascorbate, glutathione, and methimazole inhibited this process, while methionine was without effect. Inhibition by ascorbate and glutathione was associated with their oxidation to corresponding radical species by the agonists’ derived phenoxyl radicals. Using electron paramagnetic resonance (EPR), we detected free radical metabolites from β2-agonists by spin trapping with 2-methyl-2-nitrosopropane (MNP). Formation of these radicals was inhibited by pharmacologically relevant concentrations of methimazole and dapsone. In alkaline buffers, radicals from fenoterol and its structural analogue, metaproteronol, were detected by direct EPR. Analysis of these spectra suggests that oxidation of fenoterol and metaproterenol, but not terbutaline, causes their transformation through intramolecular cyclization by addition of their amino nitrogen to the aromatic ring. Together, these results indicate that phenolic β2-agonists function as substrates for airway peroxidases and that the resulting products differ in their structural and functional properties from their parent compounds. They also suggest that these transformations can be modulated by pharmacological approaches using appropriate peroxidase inhibitors or alternative substrates. These processes may affect therapeutic efficacy and also play a role in adverse reactions of the β2-agonists.<br />
Chemical research in toxicology, 22(6), pp.1137-1150.<br />
<br />
[4]. Santos, J.L., Yamasaki, P.R., Chin, C.M., Takashi, C.H., Pavan, F.R. and Leite, C.Q., 2009.<br />
Synthesis and in vitro anti Mycobacterium tuberculosis activity of a series of phthalimide derivatives.<br />
Abstract New phthalimide derivatives were easily prepared through condensation of phthalic anhydride and selected amines with variable yields (70–90%). All compounds (3a–l) were evaluated against Mycobacterium tuberculosis H37Rv using Alamar Blue susceptibility. The compounds 3c, 3i, and 3l have the minimum inhibitory concentrations (MICs) of 3.9, 7.8, and 5.0 μg/mL, respectively, and could be considered new lead compounds in the treatment of tuberculosis and multi-drug resistant tuberculosis.<br />
Bioorganic & medicinal chemistry, 17(11), pp.3795-3799.<br />
<br />
[5]. Varma, M.V., Feng, B., Obach, R.S., Troutman, M.D., Chupka, J., Miller, H.R. and El-Kattan, A., 2009.<br />
Physicochemical determinants of human renal clearance.<br />
Abstract Abstract: Kidney plays an important role in the elimination of drugs, especially with low or negligible hepatic clearance. An analysis of the interrelation of physicochemical properties and the human renal clearance for a data set of 391 drugs or compounds tested in humans is presented. The data set indicated that lipophilicity shows a negative relationship while polar descriptors show a positive relationship with renal clearance. Analysis of net secreted and net reabsorbed subsets revealed that hydrophilic ionized compounds are probable compounds to show net secretion and a possible drug−drug interaction due to their likely interaction with uptake transporters and inherent low passive reabsorption. The physicochemical space and renal clearance were also statistically analyzed by therapeutic area. In conclusion, ionization state, lipophilicity, and polar descriptors are found to be the physicochemical determinants of renal clearance. These fundamental properties can be valuable in early prediction of human renal clearance and can aid the chemist in structural modifications to optimize drug disposition.<br />
Journal of medicinal chemistry, 52(15), pp.4844-4852.
|
