Skin Absorption Databases and Predictive Equations
Richard H. Guy, Jonathan Hadgraft in Transdermal Drug Delivery, 2002
The data in Fig. 10 appear to scatter uniformly around log Pcw/Pcw,calc = 0. However, there is some indication that permeability coefficient measurements determined from acidic solutions are larger (on average) than permeability coefficient measurements determined from basic solutions. The compounds studied from acidic solutions were primarily carboxylic acids, and the compounds studied from basic solutions are primarily amines. To explore the possibility that acid-base interactions between the skin and the penetrating molecule cause this weak trend, we distinguished the stronger acids (pKa < 6.0) and the stronger bases (pKa > 6.0) from nondissociating compounds or weak acids (pKa > 6.0) and weak bases (pKa < 6.0). It appears that the pH more than a chemical acid or basic strength is responsible for the trend in Fig. 10. We neglected the measurements arbitrarily plotted at pH = 7 and regressed the residual log Pcw/Pcw,calc on pH for the 105 remaining measurements. The best-fit line, log Pcw/Pcw,calc = 1.06 − 0.146 pH, has a slope that was statistically different from zero at the 95% level of confidence, although the goodness-of-fit statistics were poor (r2 = 0.17, , RMSE = 0.66, F-ratio = 20). The data in Fig. 10 suggest that acidic conditions may weakly enhance the permeability of the SC in some way. However, many more data are needed to confirm this conclusion.
Hydrolytic Enzymes for the Synthesis of Pharmaceuticals
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
Other amidases have also been elegantly employed in the hydrolysis of amides for the synthesis of the corresponding carboxylic acids. This is the case of the desymmetrisation of 2-ethyl-2-methylmalonamide using different biocatalysts (Nojiri et al., 2015), including 21 microorganisms and 2 amidases (CsAM from Cupriavidus sp. KNK-J915 and CnAM from Cupriavidus necator JM P134). The CsAM-catalysed hydrolysis of the target prochiral diamide was successfully achieved on an 80 g-scale, so the (S)-amido acid was obtained as crude product in full conversion and >98% ee after 22 h at 32°C (Scheme 9.15). The so-obtained amide served as ideal precursor of (R)-isovaline through a chemical Hofmann rearrangement, compounds that has been reported to activate the metabotropic γ-aminobutyric acid-B receptor, acting for instance as an analgesic agent. Amidase-catalysed desymmetrisation of 2-ethyl-2-methyl-malonamide for the chemoenzymatic synthesis of (R)-isovaline.
Binders in Pharmaceutical Granulation
Dilip M. Parikh in Handbook of Pharmaceutical Granulation Technology, 2021
Low molecular weight aldehydes and carboxylic acids are found in many excipients including sugars, polymers, and unsaturated fats [18]. The most common reactive species of concern in solid dosage forms tend to be formaldehyde and its corresponding acid, formic acid. Table 4.3 lists typical levels of these impurities for various binders, granulation aids, and tableting excipients. Others include acetaldehyde, glyoxal, furfural, glyoxylic, and acetic acid. Carboxylic acids could be introduced because of not only carryover from manufacturing but also autoxidation of excipients, which, for example, leads to the formation of formaldehyde, which is then further oxidized to form formic acid. The presence of these impurities needs to be considered in acid-labile drugs as well as drugs with nucleophilic functional groups, for example, primary and secondary amines and hydroxyl groups [18,19]. Formaldehyde and formic acid have been identified as being of particular concern when using polysorbate, povidone, and polyethylene glycol [20,21].
Refining the structure−activity relationships of 2-phenylcyclopropane carboxylic acids as inhibitors of O-acetylserine sulfhydrylase isoforms
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Joana Magalhães, Nina Franko, Giannamaria Annunziato, Marco Pieroni, Roberto Benoni, Anna Nikitjuka, Andrea Mozzarelli, Stefano Bettati, Anna Karawajczyk, Aigars Jirgensons, Barbara Campanini, Gabriele Costantino
To investigate whether the carboxylic acid functionality might be modified, we replaced it with isosteric groups. Among the set of possible substituents, sulphonamides, a tetrazole ring and amides were initially investigated. While the sulphonamide group is a nonplanar isoster of the carboxylic acid, the tetrazole is planar and presents a similar acidity. On a similar vein, substituted amides were prepared because it is well known that the nature of the substituents might affect the selectivity of action toward different bacterial strains, either Gram-positive or Gram-negative29,30. For instance, in the case of sulphonamide drugs, potency and selectivity are modulated by the substituent at the amidic nitrogen31. Finally, we investigated the benzyl group attached at the C1 of the cyclopropane ring, with the aim to evaluate its substitution with heteroaromatic structures like pyridine and five-terms heteroaromatic rings, leading to molecules characterised by a lower lipophilicity.
MCL-1 inhibitors – where are we now (2019)?
Published in Expert Opinion on Therapeutic Patents, 2019
Steven Fletcher
In a continuation of their work on indole-2-carboxylic acids [18,19], Fesik’s laboratory at Vanderbilt University published patent application US20160106731, which was recently granted as US Pat. No. 9,949,965, on MCL-1 inhibitors that present a tricyclic indole core [20]. Formula 2 represents the generic structure, which is shown in Figure 2. L1 can be a covalent bond or a straight or branched C1-6 hydrocarbon chain wherein one or more CH2 units may be replaced with O, S, N(R), C(O), amide or sulfonamide. A can be O, S, S(O), S(O)2, N(R) or CH2. L2 is a covalent bond such that the indole core is directly connected to the R3 group, or may be heteroatom-substituted, or unsubstituted, alkyl linkers. R2 is, among others, a carboxylic acid, an acyl sulfonamide or an amide. The remaining R groups can be a wide range of functionalities, including akyl, aryl, halogeno, CN and NO2. In total, 34 specific compounds were presented, and of those tested, eight inhibited MCL-1 with Ki values below 100 nM (FPCA). In addition, MCL-1 vs. BCL-xL inhibitory selectivities were given: compound 2 demonstrated a > 2000-fold preference for binding MCL-1 (Ki = 9 nM) over BCL-xL (Ki > 20 μM).
Carboxylic acids accelerate acidic environment-mediated nanoceria dissolution
Published in Nanotoxicology, 2019
Robert A. Yokel, Matthew L. Hancock, Eric A. Grulke, Jason M. Unrine, Alan K. Dozier, Uschi M. Graham
Phase 2 findings, 12 weeks after initiation of dialysis/dissolution, were characterized by lack of significant change in the superstructure from Phase 1, but obvious presence of nanoceria dissolution, resulting in rounding of nanoceria crystallite edges under all carboxylic acid conditions at pH 4.5. For example, in the presence of citric acid (Figure 6(w)) nanoceria agglomerates persisted into Phase 2, but the primary crystal particles bound to each other in the agglomerates changed due to dissolution. This was evidenced by the reduction of primary particle size, and to a lesser degree reduction of the agglomerate size, creating much larger voids between primary particles, that gave the agglomerates a skeletal appearance. This was observed for all ligands, with some variability among the ligands. Ligand type did not alter the crystallinity of the primary particles as they dissolved within the agglomerates but led to smaller and more rounded nanoceria. In general, the agglomerates did not collapse or reorganize as a result of the initial dissolution process. However, some carboxylic acids (malic and lactic) caused a much greater skeletal formation in the agglomerates, due to more rapid nanoceria dissolution. This resulted in significant void formation between primary nanoceria particles. This was observed to a lesser extent for other carboxylic acids (Figure 6). The reduction of primary particle size was associated with the increasing concentration of cerium in the bath (Figure 3).
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