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Protein & Cell 2011年第8期2卷 680-688页

作者： Wenqing Shui Song Lin Allen Zhang Yan Chen Yingying Huang Mark Sanders College of Life Sciences Nankai UniversityTianjin 300071China High-Throughput Molecular Drug Discovery Center Tianjin Joint Academy of Biotechnology and MedicineTianjin 300074China Metabolism&Pharmacokinetics NovartisEmeryvilleCA 94608USA Thermo Fisher Scientific San JoseCA 95134USA

Improving analytical throughput is the focus of many quantitative workflows being developed for early drug *** drug candidate screening,it is common practice to use ultra-high performance liquid chromatography(U-HPLC)coupled with triple quadrupole mass *** approach certainly results in short analytical run time;however,in assessing the true throughput,all aspects of the workflow needs to be considered,including instrument optimization and the necessity to re-run samples when information is *** we describe a high-throughput metabolic stability assay with a simplified instrument set-up which significantly improves the overall assay *** addition,as the data is acquired in a non-biased manner,high information content of both the parent compound and metabolites is gathered at the same time to facilitate the decision of which compounds to proceed through the drug discovery pipeline.

关键词： metabolic stability high-resolution mass spectrometry accurate mass ultra-high performance liquid chromatography

Development of fluorine-substituted NH_(2)-biphenyl-diarylpyrimidines as highly potent non-nucleoside reverse transcriptase inhibitors:Boosting the safety and metabolic stability

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Acta Pharmaceutica Sinica B 2023年第3期13卷 1192-1203页

作者： Xin Jin Shuai Wang Limin Zhao Wenjuan Huang Yinxiang Zhang Christophe Pannecouque Erik De Clercq Ge Meng Huri Piao Fener Chen Engineering Center of Catalysis and Synthesis for Chiral Molecules Department of ChemistryFudan UniversityShanghai 200433China Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs Shanghai 200433China Key Laboratory of Natural Resources of Changbai Mountain&Functional Molecules Ministry of EducationCollege of PharmacyYanbian UniversityYanji 133002China Rega Institute for Medical Research KU LeuvenLeuven B-3000Belgium

Our recent studies for nonnucleoside reverse transcriptase inhibitors identified a highly potent compound JK-4b against WT HIV-1(EC_(50)=1.0 nmol/L),but the poor metabolic stability in human liver microsomes(t_(1/2)=14.6 min)and insufficient selectivity(SI=2059)with high cytotoxicity(CC_(50)=2.08μmol/L)remained major issues associated with *** present efforts were devoted to the introduction of fluorine into the biphenyl ring of JK-4b,leading to the discovery of a novel series of fluorine-substituted NH_(2)-biphenyl-diarylpyrimidines with noticeable inhibitory activity toward WT HIV-1 strain(EC_(50)=1.8–349 nmol/L).The best compound 5t in this collection(EC_(50)=1.8 nmol/L,CC_(50)=117μmol/L)was 32-fold in selectivity(SI=66,443)compared to JK-4b and showed remarkable potency toward clinically multiple mutant strains,such as L100I,K103N,E138K,and *** metabolic stability of 5t was also significantly improved(t_(1/2)=74.52 min),approximately 5-fold higher than JK-4b in human liver microsomes(t_(1/2)=14.6 min).Also,5t possessed good stability in both human and monkey *** significant in vitro inhibition effect toward CYP enzyme and hERG was *** single-dose acute toxicity test did not induce mice death or obvious pathological *** findings pave the way for further development of 5t as a drug candidate.

关键词： HIV-1 NNRTI DAPYs Safety metabolic stability

Picomolar inhibitor of reverse transcriptase featuring significantly improved metabolic stability

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药学学报:英文版 2023年第7期13卷 3054-3066页

作者： Ya-Li Sang Christophe Pannecouque Erik De Clercq Shuai Wang Fen-Er Chen Department of Chemistry Engineering Center of Catalysis and Synthesis for Chiral MoleculesFudan UniversityShanghai 200433China Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs Shanghai 200433China School of Science Harbin Institute of Technology(Shenzhen)Shenzhen 518055China Rega Institute for Medical Research KU LeuvenLeuven B-3000Belgium

Considering the undesirable metabolic stability of our recently identified NNRTI 5(t1/2=96 min)in human liver microsomes,we directed our efforts to improve its metabolic stability by introducing a new favorable hydroxymethyl side chain to the C-5 position of *** strategy provided a series of novel methylol-biphenyl-diarylpyrimidines with excellent anti-HIV-1 *** best compound 9g was endowed with remarkably improved metabolic stability in human liver microsomes(t1/2=2754 min),which was about 29-fold longer than that of 5(t1/2=96 min).This compound conferred picomolar inhibition of WT HIV-1(EC50=0.9 nmol/L)and low nanomolar activity against five clinically drug-resistant mutant *** maintained particularly low cytotoxicity(CC50=264μmol/L)and good selectivity(SI=256,438).Molecular docking studies revealed that compound 9g exhibited a more stable conformation than 5 due to the newly constructed hydrogen bond of the hydroxymethyl group with ***,compound 9g was characterized by good safety *** displayed no apparent inhibition of CYP enzymes and h *** acute toxicity assay did not cause death and pathological damage in mice at a single dose of 2 g/*** findings paved the way for the discovery and development of new-generation anti-HIV-1 drugs.

关键词： NNRTI HIV-1 DAPYs Picomolar metabolic stability

Discovery of highly selective and orally available benzimidazole-based phosphodiesterase 10 inhibitors with improved solubility and pharmacokinetic properties for treatment of pulmonary arterial hypertension

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Acta Pharmaceutica Sinica B 2020年第12期10卷 2339-2347页

作者： Yuncong Yangy Sirui Zhangy Qian Zhouy Chen Zhang Yuqi Gao Hao Wang Zhe Li Deyan Wu Yinuo Wu Yi-You Huang Lei Guo Hai-Bin Luo School of Pharmaceutical Sciences Sun Yat-sen UniversityGuangzhou 510006China

Optimization efforts were devoted to discover novel PDE10 A inhibitors in order to improve solubility and pharmacokinetics properties for a long-term therapy against pulmonary arterial hypertension(PAH)starting from the previously synthesized inhibitor *** a result,a potent and highly selective PDE10 A inhibitor,14·3 HC1(half maximal inhibitory concentration,IC50=2.8 nmol/L and>3500-fold selectivity)exhibiting desirable solubility and metabolic stability with a remarkable bioavailability of50%was identified with the aid of efficient methods of binding free energy *** PAH studies showed that the improvement offered by 14·3 HCl[2.5 mg/kg,oral administration(p.o.)]was comparable to tadalafil(5.0 mg/kg,p.o.),verifying the feasibility of PDE10 A inhibitors for the antiPAH *** crystal structure of the PDE10 A-14 complex illustrates their binding pattern,which provided a guideline for rational design of highly selective PDE10 A inhibitors.

关键词： Phosphodiesterase 10A Inhibitor Benzimidazole derivatives Crystal structure metabolic stability Bioavailability Pulmonary arterial hypertension

Evaluation of the metabolism of PEP06,an endostatin-RGDRGD 30-amino-acid polypeptide and a promising novel drug for targeting tumor cells

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Journal of Pharmaceutical Analysis 2022年第5期12卷 766-773页

作者： Liyun Niu Huiyu Zhou Yueru Lian Ya Gao Yulu Liu Ruolan Gu Zhuona Wu Xiaoxia Zhu Hui Gan Zhiyun Meng Guifang Dou State Key Laboratory of Drug Metabolism and Pharmacokinetics Department of Pharmaceutical SciencesBeijing Institute of Radiation MedicineBeijing100850China Henan University KaifengHenan475004China

PEP06 is a novel endostatin-Arg-Gly-Asp-Arg-Gly-Asp(RGDRGD)30-amino-acid polypeptide featuring a terminally fused RGDRGD hexapeptide at the N *** active endostatin fragment of PEP06 directly targets tumor cells and exerts an antitumoral ***,little is known about the kinetics and degradation products of PEP06 in vitro or in *** this study,we investigated the in vitro metabolic stability of PEP06 after it was incubated with living cells obtained from animals of different species;we further identified the degradation characteristics of its cleavage ***06 underwent rapid enzymatic degradation in multiple types of living cells,and the liver,kidney,and blood play important roles in the metabolism and clearance of the peptides resulting from the molecular degradation of *** identified metabolites of PEP06 using full-scan mass spectrometry(MS)and tandem MS(MS2),wherein 43 metabolites were characterized and identified as the degradation metabolites from the parent peptide,formed by successive losses of amino *** metabolites were C and N terminal truncated products of *** structures of 11 metabolites(M6,M7,M16,M17,M21,M25,M33,M34,M39,M40,and M42)were further confirmed by comparing the retention times of similar full MS spectrum and MS2 spectrum information with reference standards for the synthesized *** have demonstrated the metabolic stability of PEP06 in vitro and identified a series of potentially bioactive downstream metabolites of PEP06,which can support further drug research.

关键词： PEP06 HRMS metabolic stability Metabolites identification