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Zhan M.,University of Sichuan | Xu R.,University of Sichuan | Tian Y.,University of Sichuan | Jiang H.,University of Sichuan | And 4 more authors.
European Journal of Organic Chemistry | Year: 2015

A highly effective and operationally simple method for the deuteration of phenols using NaOH as a catalyst and D2O as the deuterium source is presented. A high regioselectivity for the ortho and/or para hydrogens relative to the oxygen atom was achieved, as well as a high degree of deuterium incorporation. The method also has a high functional-group tolerance, and allowed the deuteration of complex pharmaceutically interesting substrates. Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Xu R.,University of Sichuan | Zhan M.,University of Sichuan | Peng L.,University of Sichuan | Pang X.,Hinova Pharmaceuticals Inc | And 6 more authors.
Journal of Labelled Compounds and Radiopharmaceuticals | Year: 2015

Nintedanib is a novel triple angiokinase inhibitor that inhibits three growth factors simultaneously. Deuterated derivatives of nintedanib at certain metabolically active sites were prepared and evaluated in vitro and in vivo. In particular, deuterated compound SKLB-C2202 had significantly improved pharmacokinetic properties compared with nintedanib. These efforts lay the foundation for further investigating the druggability of SKLB-C2202. Deuterated derivatives of nintedanib at certain metabolically active sites were prepared and evaluated in vitro and in vivo. Deuterated compound SKLB-C2202 had significantly improved pharmacokinetic properties compared with nintedanib. Further research is underway. Copyright © 2015 John Wiley & Sons, Ltd.


Guo S.,University of Sichuan | Pang X.,CAS Chengdu Institute of Organic Chemistry | Peng L.,University of Sichuan | Zhan M.,University of Sichuan | And 5 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2015

Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-1(VEGFR1), -2(VEGFR2), and -3(VEGFR3). Analog of Tivozanib with deuterium-for-hydrogen replacement in metabolically active site was prepared and evaluated in vitro. Compared to its prototype, deuterated Tivozanib compound HC-1144 retained in vitro activity against VEGFR tyrosine kinases. In vivo pharmacokinetic studies indicated HC-1144 clearly altered the blood circulation behavior, which was proved by significantly prolonged blood circulation half life time (t1/2) and increased AUC0-∞. Therefore, HC-1144 has the potential to be a novel inhibitor against VEGFR tyrosine kinases with long-acting plasma exposure. © 2015 Elsevier Ltd. All rights reserved.


Jiang J.,CAS Shanghai Institute of Materia Medica | Jiang J.,University of Chinese Academy of Sciences | Pang X.,University of Chinese Academy of Sciences | Pang X.,CAS Chengdu Institute of Organic Chemistry | And 14 more authors.
Drug Design, Development and Therapy | Year: 2016

Background: The replacement of hydrogen with deuterium invokes a kinetic isotope effect. Thus, this method is an attractive way to slow down the metabolic rate and modulate pharmacokinetics. Purpose: Enzalutamide (ENT) acts as a competitive inhibitor of the androgen receptor and has been approved for the treatment of metastatic castration-resistant prostate cancer by the US Food and Drug Administration in 2012. To attenuate the N-demethylation pathway, hydrogen atoms of the N–CH3 moiety were replaced by the relatively stable isotope deuterium, which showed similar pharmacological activities but exhibited favorable pharmacokinetic properties. Methods: We estimated in vitro and in vivo pharmacokinetic parameters for ENT and its deuterated analog (d3-ENT). For in vitro studies, intrinsic primary isotope effects (KH/KD) were determined by the ratio of intrinsic clearance (CLint) obtained for ENT and d3-ENT. The CLint values were obtained by the substrate depletion method. For in vivo studies, ENT and d3-ENT were orally given to male Sprague Dawley rats separately and simultaneously to assess the disposition and metabolism of them. We also investigated the main metabolic pathway of ENT by comparing the rate of oxidation and hydrolysis in vitro. Results: The in vitro CLint (maximum velocity/Michaelis constant [Vmax/Km]) of d3-ENT in rat and human liver microsomes were 49.7% and 72.9% lower than those of the non-deuterated compound, corresponding to the KH/KD value of ~2. The maximum observed plasma concentration, Cmax, and area under the plasma concentration -time curve from time zero to the last measurable sampling time point (AUC0–t) were 35% and 102% higher than those of ENT when orally administered to rats (10 mg/kg). The exposure of the N-demethyl metabolite M2 was eightfold lower, whereas that of the amide hydrolysis metabolite M1 and other minor metabolites was unchanged. The observed hydrolysis rate of M2 was at least ten times higher than that of ENT and d3-ENT in rat plasma. Conclusion: ENT was mainly metabolized through the “parent→M2→M1” pathway based on in vitro and in vivo elimination behavior. The observed in vitro deuterium isotope effect translated into increased exposure of the deuterated analog in rats. Once the carbon–hydrogen was replaced with carbon–deuterium (C–D) bonds, the major metabolic pathway was retarded because of the relatively stable C–D bonds. The systemic exposure to d3-ENT can increase in humans, so the dose requirements can be reduced appropriately. © 2016 Jiang et al.


Zhan M.,University of Sichuan | Jiang H.,University of Sichuan | Pang X.,Hinova Pharmaceuticals Inc | Zhang T.,University of Sichuan | And 6 more authors.
Tetrahedron Letters | Year: 2014

A highly effective and operationally practical method for the regioselective deuteration of N-alkyl-substituted anilines employing Ru3(CO)12(≤1 mol %) as catalyst and D2O as deuterium source was described. A variety of N-alkyl-substituted anilines were efficiently deuterated (up to 98%) at the ortho and/or para position with respect to the nitrogen at neutral conditions. Under the present conditions, deuterated anilines can be easily obtained with simple extraction and evaporation. Substituents with aromatic methoxy groups would not influence the selectivity compared to previous method. © 2014 Elsevier Ltd. All rights reserved.

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