Special Problems with Biological Fluids
Joseph Chamberlain in The Analysis of Drugs in Biological Fluids, 2018
Aromatic amines are hydroxylated to the corresponding hydroxylamino compounds; sulfanilamide is hydroxylated at the N4-amino group to give p-hydroxylaminobenzenesulfonamide (Figure 2.5).166 Tertiary amines may be oxidized to the N-oxide, the main route of metabolism of the benzodiazepine, loprazolam (Figure 2.6).167 Secondary amines are dealkylated to primary amines and the corresponding aldehyde (Figure 2.7). Thioethers are converted by oxidation to sulfoxides, an example being the metabolism of the phenothiazine, quinuclidinyl-3-methyl-10-phenothiazine (Figure 2.8).168,169 Thiones may be oxidized to the corresponding oxo compound as in the metabolism of thiobarbital to barbital (Figure 2.9).170 Metabolism is sometimes reversible as for example in the interconversion of 4-amino-5-chloro-2-[(methylsulfinyl)ethoxy]-N[2-(diethylamino)ethyl]benzamide and its sulfide and sulfone metabolites in rats.171
The Chemical Cross-Linking of Peptide Chains
Roger L. Lundblad, Claudia M. Noyes in Chemical Reagents for Protein Modification, 1984
The next general class of reagents that we will discuss is the homobifunctional imidoesters (Figure 8). This class of reagents was introduced by Singer and co-workers.35 These reagents have the advantage that the reaction with the protein results in charge preservation of the lysine residue modified. This class of reagents is highly specific for primary amines in the following reactions as shown in Figures 9 and 10. Aspects of the chemistry of this reaction are further discussed in Volume I, Chapter 10. Buffer effects on the reaction have not been extensively investigated except to specify that the use of potential competing nucleophiles (e.g., Tris, imidazole) should be avoided. Most studies have used 0.02 to 0.1 M triethanolamine in the range of pH 8.0 to 9.0. It has been suggested that the amidation reaction is enhanced by the presence of triethanolamine in studies on the reaction of methyl-4-mercaptobutyrimidate.22 The greatest use of these reagents has been in the study of protomer organization of oligomeric proteins and self-association systems.
Xenobiotic Biotransformation
Robert G. Meeks, Steadman D. Harrison, Richard J. Bull in Hepatotoxicology, 2020
Xenobiotics or endogenous compounds containing amino, hydroxyl, or sulfhydryl groups are substrates for acetyltransferases [reviewed by King and Glowinski (1983) and Weber and Hein (1985)]. Amines, including aromatic and aliphatic primary amines, hydrazines, hydrazides, and sulfonamides, have been the most widely studied substrates. Endogenous substrates are 5-hydroxy-tryptamine and histamine. The enzymes are cytosolic and are present in several tissues; liver has the highest activity. Acetyl coenzyme A is the co-factor. The enzymes have been designated acetyl CoA: amine acetyl transferases. Sulfamethazine N-acetyltransferase is another term for the enzyme activity; sulfamethazine is the prototype substrate. The activity is characterized by polymorphism across many species, and individuals (or species and strains) are characterized as “slow” or “fast” acetylators. This polymorphism is determined by a single gene locus containing two co-dominant alleles: R = rapid, and r = slow. This polymorphism is an important determinant of susceptibility to toxicity and carcinogenicity of drugs (e.g., isoniazid) or xenobiotics, particularly aromatic amines, which are bioactivated or detoxified by acetylation.
Pharmacokinetic evaluation of quetiapine fumarate controlled release hybrid hydrogel: a healthier treatment of schizophrenia
Published in Drug Delivery, 2018
Muhammad Akhlaq, Faiza Maryam, Abdelhamid Elaissari, Hashmat Ullah, Muhammad Adeel, Abid Hussain, Muhammad Ramzan, Obaid Ullah, Muhammad Zeeshan Danish, Shehla Iftikhar, Nighat Aziz
Swelling increases as the quantity of Gel increases. The functional groups of Gel responsible for swelling of hydrogels are amine (–NH2) and carboxylic acid group (–COOH) (Raafat, 2010). Amine contains basic nitrogen and is basically a derivative of ammonia with one or more hydrogen atom(s) replaced by alkyl or aryl group. At pH below pKb of basic components (acidic pH), ionization (protonation) occurs that results in formation of –NH3+ ions and due to the presence of similar cations, electrostatic repulsion takes place within them resulting in swelling of hydrogel in acidic medium (Gil et al., 2005). Gel also contains -COOH group which is an acidic component and at pH above pKa (basic medium) loses H + ion thus becomes COO−, ionization of COOH group at pH 7.4 causes the repulsion of anions due to electrostatic repulsion and thus swelling of the hydrogel occurs in basic medium. Because of the presence of these functional groups, Gel/HPMC hydrogel showed swelling at both acidic and basic pH (Lou & Chirila, 1999).
PDE1 inhibitors: a review of the recent patent literature (2008-present)
Published in Expert Opinion on Therapeutic Patents, 2022
Mei-Ling Le, Mei-Yan Jiang, Chuan Han, Yi-Yi Yang, Yinuo Wu
In 2015, Kehler and coworkers disclosed a series of PDE1 inhibitors with quinazoline scaffold (Figure 27). The X group on the quinazoline was a halogen atom in the first patent. The IC50 values of these compounds against PDE1 ranged from 7 nM to 2800 nM. Most compounds in this patent had two or more stereoisomers and one showed better inhibitory activities than others [79]. For the representative compound 86, stereoisomer 1 gave the IC50 value of 9.9 nM, while stereoisomer 2 gave the IC50 value of 65 nM against PDE1B. However, no configuration was provided for each stereoisomer. In another patent by Kehler, the X group on the quinazoline was instead by the methoxy group. The amine can be primary amine, secondary amine, or cyclic aliphatic amine [80]. The configuration had a significant impact on the inhibitory activities. For example, the (S)-87 was 30-fold more potent against PDE1B than (R)-87 [81].
Evaluation of WO2017098421: GSK’s benzothiazine compounds as CD73 inhibitor filings
Published in Expert Opinion on Therapeutic Patents, 2018
Ya-Ping Gong, Ren-Zhong Wan, Zhao-Peng Liu
The Markush claims of this application encompass substituted benzothiadiazine derivatives (2) and define a variety of potential substituents on the benzothiadiazine core. A total of 187 compounds are specifically claimed. In the majority of these, the substituted amine at the 3-position (R-NH-) is an arylamine (generally alkylbenzene, phenol, halogenobenzene) or a bicycloheteroarylamine (generally indole, indazol). Though broad claims are made for the R1 and R2, the R1 is absent in nearly all the examples and only a small number of examples are provided in which R1 is H, while the R2 is either a methoxy or, more commonly, a hydroxyl group. Further claims cover the capsule, injection, and tablet compositions containing them, the processes for their preparation, and their applications in CD73-mediated diseases and specifically for cancers.Chlorosulfonyl isocyanate, AlCl3, 1-nitropropane, 110°C, 30 min.POBr3, acetonitrile, 80°C, overnight or 100°C, 3 days.DMF, NCS, RT, 2 days.BBr3, DCM, 50°C, 5 h.1H-indazol-4-amine, K3PO4 or KH2PO4, n-BuOH, 90°C, 3 h.