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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
One example is the agent branaplam (Figure 5.100) which, as of July 2019, is in Phase I/II clinical trials for the treatment of children with Spinal Muscular Atrophy, branaplam is in a Phase II clinical trial SMA type 1. This molecule, based on a pyridazine building block, enhances the inclusion of exon 7, resulting in a full length and functional protein product. It represents the first example of splicing modulation using a sequence-selective small molecule and works by stabilizing the transient double-stranded RNA (dsRNA) structure formed between the SMN2 pre-mRNA and the U1 snRNP complex, a key component of the splicesome. It also increases the binding affinity of U1 snRNP to the 5’ splice site (5’ss) in a sequence-selective manner. Structure of branaplam (showing the keto-enol tautomers) which, as of July 2019, is in Phase I/II clinical trials for the treatment of children with spinal muscular atrophy (SMA).
Structures of benzodiazepine recognition site ligands
Published in Adam Doble, Ian L Martin, David Nutt, Calming the Brain: Benzodiazepines and related drugs from laboratory to clinic, 2020
Adam Doble, Ian L Martin, David Nutt
Synthesis, pharmacology and structure-activity data have been reported for the series of 1,2,4-triazolo[4,3-b]pyridazines, a class of compound with activity in tests predictive of anxiolytic activity (Albright et al, 1981). Figure 5.7 shows CL 218,872, the most widely studied member of the series.
Selection Considerations for Membranes and Models for In Vitro/Ex Vivo Permeation Studies
Published in Tapash K. Ghosh, Dermal Drug Delivery, 2020
Pei-Chin Tsai, Tannaz Ramezanli, Dina W. Ameen, Sonia Trehan, Nathaly Martos, Zheng Zhang, Bozena Michniak-Kohn
PDMS membrane has been used extensively to simulate and predict drug permeability to skin. One of the early foci was to investigate the effect of atomic charge on a compound’s permeability. Chen et. al. reported an empirical model for drug permeation for aromatic compounds through PDMS using molecular modeling.75 A total of 103 compounds in 15 ring classes, including benzene, quinoline, naphthalene, pyridine, naphthyridine, furan, benzofuran, imidazole, benzimidazole, indole, thiophene, pyrrole, pyrazole, pyridazine and pyrazine were studied. In this study flux was found to be significantly affected by atomic charge. Partial charge calculations combined with solubility and molecular weight provided a universal quantitative structure-transportability relationship (QSTR) model for the estimation of flux for all 15 classes of compounds. Later, the same research group refined the model and studied the maximum steady-state flux of 171 compounds through PDMS membranes.76 The results further demonstrated that the simple QSTR equation is capable of accurately predicting the steady-state flux of a variety of compounds. Contribution of atomic charge to mass transport phenomena was further verified by the prediction of the apparent permeability calculated from the steady-state flux data.
Thais savignyi tissue extract: bioactivity, chemical composition, and molecular docking
Published in Pharmaceutical Biology, 2022
Mohamed R. Habib, Ahmed A. Hamed, Rasha E. M. Ali, Khaled M. Zayed, Rasha M. Gad El-Karim, Rehab Sabour, Hanaa M. Abu El-Einin, Mosad A. Ghareeb
Furthermore, pyridazine derivatives have been reported to have diverse biological activities, including antiviral, anticancer, and antimicrobial properties (Butnariu and Mangalagiu 2009). Quinoline derivatives have diverse biological activities and constitute an important class of compounds for new drug development (Orhan Puskullu et al. 2013). Various synthetic quinoline derivatives were screened for their biological activities. Some derivatives showed antibacterial (Narender et al. 2006; Reddy et al. 2009; Matada et al. 2021), antifungal (Musiol et al. 2006), and cytotoxic activity (Costa et al. 2020). Phenanthrenes are a relatively small group of natural products derived primarily from plants. Almost all of the phenanthrene compounds isolated from plants demonstrated a variety of biological activities, including antioxidants (Behery et al. 2013; Woo et al. 2014), antimicrobial (Guo et al. 2016; Tóth et al. 2016), and cytotoxicity (Ma et al. 2016). Other chemical classes represented in Ts-EtOAc extract, such as ketones, monoterpenes, fatty acid esters, stilbenoids, and sesquiterpenoids, have been shown to have beneficial biological activities (Mallesha et al. 2012; Abdel-Aziz et al. 2018; Akinwumi et al. 2018; Mothana et al. 2018; Ghareeb et al. 2019; Elkhouly et al. 2020). Hamed et al. 2020;
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.
Hedgehog signaling pathway inhibitors: an updated patent review (2015–present)
Published in Expert Opinion on Therapeutic Patents, 2020
Deborah Quaglio, Paola Infante, Lucia Di Marcotullio, Bruno Botta, Mattia Mori
Researchers at Redx Pharma Ltd in the United Kingdom (UK) reported three patents disclosing various heterocyclic compounds (Figure 9) as low-nanomolar inhibitors of the Hh signaling pathway, which are structurally related to SMO antagonists in clinical trials (e.g. LY-2,940,680, NVP-LEQ506, and PF-04449913). The first patent provided ~170 tetrasubstituted pyridazines containing a piperidine linker as Hh inhibitors in NIH3T3-GRE-luc cells, represented by compounds 23 (IC50 = 0.05 nM), 24 (IC50 = 0.99 nM), 25 (IC50 = 0.71 nM), 26 (IC50 = 0.66 nM), and 27 (IC50 = 0.04 nM) [66]. A second patent described several benzimidazole derivatives featuring a piperidine linker. However, Hh inhibitory activity was specifically reported for 28 (IC50 = 1.21 nM) and 29 (IC50 = 22.42 nM) [67]. Finally, Redx Pharma also reported a series of tetrasubstituted pyridazines as potent inhibitors of the Hh pathway represented by 30 (IC50 = 0.71 nM), 31 (IC50 = 0.35 nM) and 32 (IC50 = 0.45 nM) [68]. Although these compounds were supposed to target SMO based on the structural similarity with well-established SMO antagonists, their direct interaction with the 7-pass transmembrane receptor was not reported in the patents, or in the scientific literature.