Antihistamines, Decongestants, and Expectorants during Pregnancy
“Bert” Bertis Britt Little in Drugs and Pregnancy, 2022
Piperidine was discovered in 1850 and is a substrate in the manufacture of several classes of drugs (SSRIs, antipsychotics, vasodilators), including antihistamines. Birth defects were not increased in frequency among 127 infants exposed to azatadine during the first trimester (Gilbert et al., 2005). The frequency of congenital anomalies was not increased among 285 infants whose mothers took cyproheptadine during embryogenesis (Gilbert et al., 2005; see Table 11.3). No epidemiological studies of birth defects or adverse fetal effects among infants born to mothers who took diphenylpyraline during pregnancy are published. Animal teratology studies of cyproheptadine are not consistent (de la Fuente and Alia, 1982; Rodriguez-Gonzalez et al., 1983; Weinstein et al., 1975), making it impossible to interpret the findings. No animal teratology studies of azatadine are published.
Other Sleep Modulators
Shojiro Inoué in Biology of Sleep Substances, 2020
Piperidine (see Figure 1) is a biogenic amine and a normal constituent of the central nervous system of both invertebrates and vertebrates, and regarded as a neuromodulator or a hypnogenic substance.1 This substance is also widely distributed in the peripheral organs. Kasé et al.2 demonstrated that piperidine intraperitoneally (i.p.) injected at doses of 40 and 80 mg/kg induced pronounced sedation and prolongation of hexobarbital-induced narcosis in mice. They also suggested that piperidine may act as a stimulator of the nicotinic cholinergic receptor. Stepita-Klauco et al.3 found that brain concentrations of piperidine increased to 36.6 nmol/g during dormancy from 2.0 nmol/g during the active state in mice. The brain content of piperidine also increased during dormancy or hibernation in snails.4 Miyata et aj 5,6,9-12 Qkano et al.,7,8 and Aisaka et al.13 studied extensively the biological and pharmacological properties of piperidine, such as its hypnogenic activity;5 its concentrations in the brain,6 7 blood,8 and urine;8 its changes in brain levels depending on seasonal activity,9 anesthesia,10,12 or sleep deprivation;12 and its vasodilating activity.13
Asymmetric Reduction of C=N Bonds by Imine Reductases and Reductive Aminases
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
6-substituted piperidines 114 (R=H) and 5-substituted pyrrolidines can be prepared by generating a ketoaldehyde from a keto acid 109 by a CAR and its subsequent amination to 111 using an amine transaminase (France et al., 2016). A final reduction step of the cyclized imine intermediate 112 by an IRED furnishes the secondary amine 114 (Fig 14.15b). This cascade could also be performed in a single E. coli cell producing a balanced amount of the required enzymes (Hepworth et al., 2017). Also 2,3-disubstituted piperidines 114 (R=Me) could be synthesized, although the amination generates a terminal amine in this case, yielding the chiral 2,3-substituted piperideine. The IRED then converted preferentially one enantiomer while introducing the second stereo center. A racemization of the imine is possible via imine 112-enamine 113 tautomerization: the desired product could be generated with 81% de and 81% ee at 86% conversion (Fig 14.15b). By employing optically pure substituted keto acids, 2,5- and 2,4-disubstituted piperidines were also accessible.
Research progress of natural products and their derivatives against Alzheimer’s disease
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Jin-Ying Liu, Hong-Yan Guo, Zhe-Shan Quan, Qing-Kun Shen, Hong Cui, Xiaoting Li
Piperine is a piperidine alkaloid with a relatively simple structure and one of the main physiologically active components of piperine and longan. Piperine is currently used clinically as a spectral anticonvulsant. In addition, Masoomeh et al. showed that long-term treatment with piperine reduced oxidative damage of rats intracerebroventricularly (ICV) injected with STZ82. Furthermore, it reduced the synaptic toxicity of STZ in the hippocampus, thereby exerting a neuroprotective effect. Suresh et al. showed that intraperitoneal injection of piperine in diabetic rats not only improved memory in diabetic rats, but also reduce AD-related BACE1, PSEN1, APAF1, CASPASE3, and CATALASE gene expression83. Hsieh et al. also found that piperine protects hippocampal neurons by upregulating protein kinase B (Akt) and glycogen synthase kinase 3β (GSK-3β) signalling pathways in the hippocampus and reducing kainate (KA)- induced excitotoxicity84. Studies have also shown that piperine can inhibit the pathological changes in AD in multiple ways and can be used as a potential anti-AD drug (Figure 13).
Recent in vivo advances of spirocyclic scaffolds for drug discovery
Published in Expert Opinion on Drug Discovery, 2022
Vasco F. Batista, Diana C. G. A. Pinto, Artur M. S. Silva
While the use of spirocyclic compounds is already common, some scaffolds are more frequently used than others. Compounds containing five- and six-membered rings prevail, commonly containing a carbon spiro center. The inclusion of at least a heteroatom is almost always required, with a clear preference for nitrogen. While a more defined outline of the spiro field is not feasible, some ring systems clearly stood out within this review. Ozonide derivatives connected to both an adamantane and a cyclohexane ring through quaternary carbon centers are recurring choices in treating a broad range of infections. Piperidine rings also see widespread use due to their ease of synthesis and functionalization. Curiously, imidazolinone and pyrrolidone derivatives were also very common, as a regular amidation reaction can build these heterocycles. Not surprisingly, the presence of nitrogen heterocycles is indeed ubiquitous within the field. As so, it may be time to increase our efforts on other, more complex, ring systems and search for activity with other heteroatoms.
Multicomponent reactions (MCR) in medicinal chemistry: a patent review (2010-2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Hafiza Amna Younus, Mariya Al-Rashida, Abdul Hameed, Maliha Uroos, Uzma Salar, Sobia Rana, Khalid Mohammed Khan
In the first step vinylation of a ketone using an appropriate vinyl metal nucleophile leads to a racemic piperidone. This is followed by 1,4-conjugated vinyl addition using metal salts of vinyl trifluoroborates, vinyl alkoxysilanes, or vinyl boronic acid/ester. A racemic amino acid derivative is prepared from the piperidone using multicomponent reactions such as the Ugi reaction, the Bucherer-Bergs reaction, or the Strecker reaction. With the help of column chromatography using a chiral stationary phase, the racemic amino acid derivatives can be resolved into enantiomerically pure isomers. The piperidine derivative is obtained by deprotection which is then benzylated. Hydroboration is done using pinacol borane or bis(pinacolato) diboron in the presence of a suitable catalyst. Hydrolysis of the amide to the amino acid derivative is done, followed by protection to form Boc-amino acid, subsequent deprotection, and amidation leads to the preparation of the final compound as shown in Scheme 10.
Related Knowledge Centers
- Alkaloid
- Amine
- Black Pepper
- Ethanol
- Organic Compound
- Piperine
- Pyridine
- Sodium
- Methylene Bridge
- Solenopsin