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Drug Design, Synthesis, and Development
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Stereochemistry is an important consideration when designing drugs, as chirality can have important implications for drug metabolism. Metabolic enzymes can often distinguish between two enantiomers, such that each can undergo different reactions. This means that testing each enantiomer separately during screening is necessary and may mean that the design of a drug may need an asymmetric synthesis.
Biotransformation of Sesquiterpenoids, Ionones, Damascones, Adamantanes, and Aromatic Compounds by Green Algae, Fungi, and Mammals
Published in K. Hüsnü Can Başer, Gerhard Buchbauer, Handbook of Essential Oils, 2020
Yoshinori Asakawa, Yoshiaki Noma
Asarone (558) and dihydroeugenol (562) were not biotransformed by A. niger. However, dihydroasarone (559) and methyl dihydroeugenol (563) were biotransformed by the same fungus to produce a small amount of 2-hydroxy (560, 561) and 2-oxo derivatives (564, 565), respectively. The chirality at C2 was determined to be R and S mixtures (1:2) by the modified Mosher method (Takahashi, 1994) (Figure 23.160).
Toxicology Through a Looking Glass: Stereochemical Questions and Some Answers
Published in Steven H. Y. Wong, Iraving Sunshine, Handbook of Analytical Therapeutic Drug Monitoring and Toxicology, 2017
Enantiomers are molecules which have the same chemical composition and only differ from one another in their three-dimensional structure. Enantiomers are related to each other as non-superim-posable mirror images in the same manner as your right and left hands (thus the term “chirality” which is derived from the Greek word for hand ”chiros”).
An updated patent review of autotaxin inhibitors (2017–present)
Published in Expert Opinion on Therapeutic Patents, 2021
Zehui Tan, Hongrui Lei, Ming Guo, Yuxiang Chen, Xin Zhai
Mitsubishi Tanabe Pharma Corporation has claimed a class of 2-aminopyrimidine derivatives in 2015 which has been reported in a previous review [15,80]. Starting from 2-aminopyrimidines, the same company developed a range of novel ATX inhibitors bearing pyridazine and pyridine scaffold by bioisosterism strategies [81]. Pyridazine analog 24 presented in vitro human ATX inhibitory activity with IC50 value of 1 nM (LPC assay) and significantly inhibited ex vivo plasma ATX activity by 91% at a dose of 1.0 mg/kg oral administered to Wistar rat. Of note, the replacement of pyridazine scaffold with pyridine leads to a slightly decrease in potency, pyridine analog 25 inhibited the enzyme with an IC50 value of 5 nM (LPC assay) and plasma ATX activity by 82%, suggesting that pyridazine scaffold is beneficial for activity. Furthermore, chirality seems to be less important for these molecules for that the (S, S)-enantiomers on cyclopropane is slightly higher than (R, R)-enantiomers in potency. In addition, Inhibitaxin Limited covered several pyridazine analogs in the patent, as well[82]. Typically, 26 exerted ATX inhibition with an IC50 value of 14.0 nM in the FS-3 assay.
Chiral mesoporous silica synthesized by a facile strategy for loading and releasing poorly water-soluble drug
Published in Drug Development and Industrial Pharmacy, 2020
Zibin Gao, Xiaoqian Lv, Yufei Fu, Xianghuan Zang, Yongjun Sun, Shuo Li, Huimin Zhang, Shanlin Qiao, Long Wang, Yanping Sun
The spiral structure is one of the most common forms in nature [1]. The channel of the CMS exhibits spiral shape with uniform distribution, which is different from the straight channel of the conventional MSN. In recent years, the chiral porous materials have been widely applied in contribution [2], functionalization [3], enantiomeric recognition and asymmetric separation [4,5], and attracted much attention. Chirality is difficult to form on inorganic materials compared to organic materials. An easy way to solve this problem is to include the organic chiral element in the inorganic system by using it as a ligand, intermediate, or template [6]. Generally, CMS can be synthesized by cooperative self-assembly of chiral or achiral amphiphiles and the silica precursors. Most of the researchers applied chiral amphiphile as templating agents to synthesize CMS [7–9], while the reports about achiral amphiphile as a template are relatively less. Wu et al. synthesized CMS by using the achiral anionic surfactant sodium lauryl sulfate and an adjuvant [10]. Han et al. also used achiral amphiphiles as the template. However, they synthesize induced the chirality of the CMS by the high concentration ammonia solution rather by the amphiphiles. Meanwhile, the particle morphology and screw pitch of the material can be controlled by changing the concentration of aqueous ammonia solution [1].
Chirality and neuropsychiatric drugs: an update on stereoselective disposition and clinical pharmacokinetics of bupropion
Published in Xenobiotica, 2018
Ranjeet Prasad Dash, Rana Rais, Nuggehally R. Srinivas
Chiral centers (centers of asymmetry) in therapeutics predispose the formation of enantiomers which may vary from one another noticeably with respect to pharmacodynamic and/or PK properties (Alkadi & Jbeily, 2017; Baker & Prior, 2002; Nguyen et al., 2006; Williams & Lee, 1985). With respect to chirality, bupropion exists as a racemic mixture, the (+)- and (–)-enantiomers (Carroll et al., 2014). Musso et al. (1993) determined the biological activity of the enantiomers and observed that the (+)- and (–)-isomers of bupropion had ED50 values of 23 and 17 mg/kg (following intraperitoneal administration), respectively, compared to 18 mg/kg for racemic bupropion in the tetrabenazine test (Musso et al., 1993). Bupropion and its two enantiomers were found to be weak (IC50 in µM level) dopamine and norepinephrine uptake inhibitors as observed from the in vitro studies (Musso et al., 1993). Preclinical studies showed that (–)-bupropion racemizes in vivo, thus indicating that the privation of greater enantiomeric specificity in the earlier studies may be due to racemization (Musso et al., 1993). However, due to the rapid racemization, limited studies have been focused towards the individual isomers.