1.Discovery, Synthesis, and Optimization of Diarylisoxazole-3-carboxamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore.
Roy S1, Šileikytė J2, Schiavone M2, Neuenswander B1, Argenton F3, Aubé J1, Hedrick MP4, Chung TD4, Forte MA5, Bernardi P6, Schoenen FJ7. ChemMedChem. 2015 Oct;10(10):1655-71. doi: 10.1002/cmdc.201500284. Epub 2015 Aug 18.
The mitochondrial permeability transition pore (mtPTP) is a Ca(2+) -requiring mega-channel which, under pathological conditions, leads to the deregulated release of Ca(2+) and mitochondrial dysfunction, ultimately resulting in cell death. Although the mtPTP is a potential therapeutic target for many human pathologies, its potential as a drug target is currently unrealized. Herein we describe an optimization effort initiated around hit 1, 5-(3-hydroxyphenyl)-N-(3,4,5-trimethoxyphenyl)isoxazole-3-carboxamide, which was found to possess promising inhibitory activity against mitochondrial swelling (EC50 <0.39 μM) and showed no interference on the inner mitochondrial membrane potential (rhodamine 123 uptake EC50 >100 μM). This enabled the construction of a series of picomolar mtPTP inhibitors that also potently increase the calcium retention capacity of the mitochondria. Finally, the therapeutic potential and in vivo efficacy of one of the most potent analogues, N-(3-chloro-2-methylphenyl)-5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxamide (60), was validated in a biologically relevant zebrafish model of collagen VI congenital muscular dystrophies.
2.Preparation of cationic starch microspheres and study on their absorption to anionic-type substance.
Zheng J1, Wang Y1, Feng Z2, Kuang Z1, Zhao D1, Jiao X1. Water Sci Technol. 2015;71(10):1545-53. doi: 10.2166/wst.2015.137.
Cationic starch microspheres (CSMs) were prepared from lab-made neutral starch-based microspheres using a cationic adsorbent, namely 3-chloro-2-hydroxypropyltrimethyl ammonium chloride, as the cationic etherifying agent. Detection by scanning electron microscopy, Fourier transform infrared spectroscopy (FTIR), and laser diffraction techniques revealed that CSMs had coarse surfaces with good sphericity and dispersibility. Differential thermal analysis showed the lower thermostability of the CSMs' main chains. Furthermore, scores of experiments confirmed that CSMs are capable of absorption to N-(phosphonomethyl) iminodiacetic acid (PMIDA), a type of anionic substance, which is the intermediate to the preparation of glyphosate, maximally up to 95.24 mg/g. Compared with the Freundlich isotherm model, the Langmuir isotherm model can better describe the absorption process. The kinetic study showed that the pseudo-second-order model demonstrated a better correlation of the experimental data in contrast with the pseudo-first-order model.
3.Quaternary Lidocaine Derivative QX-314 Activates and Permeates Human TRPV1 and TRPA1 to Produce Inhibition of Sodium Channels and Cytotoxicity.
Stueber T1, Eberhardt MJ, Hadamitzky C, Jangra A, Schenk S, Dick F, Stoetzer C, Kistner K, Reeh PW, Binshtok AM, Leffler A. Anesthesiology. 2016 Feb 9. [Epub ahead of print]
BACKGROUND: The relatively membrane-impermeable lidocaine derivative QX-314 has been reported to permeate the ion channels transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential cation channel, subfamily A, member 1 (TRPA1) to induce a selective inhibition of sensory neurons. This approach is effective in rodents, but it also seems to be associated with neurotoxicity. The authors examined whether the human isoforms of TRPV1 and TRPA1 allow intracellular entry of QX-314 to mediate sodium channel inhibition and cytotoxicity.
4.Discovery and Evaluation of Clinical Candidate AZD3759, a Potent, Oral Active, Central Nervous System-Penetrant, Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor.
Zeng Q1, Wang J1, Cheng Z1, Chen K1, Johnström P2,3, Varnäs K3, Li DY1, Yang ZF1, Zhang X1. J Med Chem. 2015 Oct 22;58(20):8200-15. doi: 10.1021/acs.jmedchem.5b01073. Epub 2015 Oct 9.
Recent reports suggest that an increasing number of patients with lung cancer, especially those with activating mutations of the epidermal growth factor receptor (EGFR), also present with brain metastases and leptomeningeal metastases. These patients have poor prognosis as there are no approved drugs for these indications. Available agents have poor efficacy for these patients even at well above their standard dose. Herein, we report the discovery of (4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl (2R)-2,4-dimethylpiperazine-1-carboxylate 1m (AZD3759), an investigational drug currently in Phase 1 clinical trial, which has excellent central nervous system penetration and which induces profound regression of brain metastases in a mouse model.