Evaluation of Deuterium-Labeled JNJ38877605: Pharmacokinetic

Oct 4, 2018 - c-Met inhibitor JNJ38877605 has proven curative as an antitumor agent, while its clinical study was terminated due to renal toxicity...
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Evaluation of Deuterium-Labeled JNJ38877605: Pharmacokinetic, Metabolic, and in Vivo Antitumor Profiles Zhengsheng Zhan,†,§ Xia Peng,‡,§ Yiming Sun,‡ Jing Ai,*,† and Wenhu Duan*,† †

Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China ‡ Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China Downloaded via UNIV OF SUNDERLAND on October 17, 2018 at 01:37:08 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

S Supporting Information *

ABSTRACT: c-Met inhibitor JNJ38877605 has proven curative as an antitumor agent, while its clinical study was terminated due to renal toxicity. It was reported that the renal toxicity was caused by the poor solubility of its aldehyde oxidase (AO) metabolites. Therefore, blocking AO oxidation of JNJ38877605 might diminish the toxic metabolites and overcome the renal toxicity. Compound 3, the AO metabolic site deuterated JNJ38877605, was then synthesized as the target molecule. In vitro monkey liver S9 fraction incubation of 3 manifested that the renal toxic metabolite M2-2 was significantly reduced, which connoted that this deuteration has partly blocked AO oxidation. After po. nasal gavage to cynomolgus monkeys, compound 3 revealed decreased AO metabolites M2-2 and M3-2 in the plasma as well as 1.88-fold AUC and 1.56-fold Cmax compared with JNJ38877605, indicating that deuterium replacement significantly blocked AO metabolism in vivo. Besides, metabolic profiles of 3 were investigated by analysis of the plasma and the urine of the po. administrated cynomolgus monkeys. Moreover, after oral administration to the EBC-1 tumor-bearing nude mice, compound 3 exhibited a better antitumor efficacy than JNJ38877605. In conclusion, deuteration on the AO metabolic site of JNJ38877605 improved its AO metabolism, oral exposure, as well as in vivo antitumor efficacy.

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INTRODUCTION c-Met, also known as hepatocyte growth factor receptor (HGFR), plays an important role in the invasive growth during embryonic development, wound healing, and tissue repair in the healthy individuals.1−3 Deviant c-Met signaling mediates tumor progression and metastasis. Consequently, many approaches have been adopted to suppress the aberrant c-Met axis as the antitumor strategy.4−6 Among them, small-molecule inhibitors have attracted considerable attention.7,8 JNJ38877605 (1) has proven effective in both preclinical and clinical antitumor studies, while its clinical trial was terminated due to the poor solubility of its aldehyde oxidase (AO) metabolites (2a, 2b) causing renal toxicity (Figure 1).9,10 Aldehyde oxidase is a molybdenum-containing hydroxylase mainly situated at the cytosolic compartment of cells that catalyzes the oxidation of aldehydes and aromatic azaheterocycles, such as pyridines, pyrimidines, benzimidazoles, and etc.11,12 AO related metabolic inactivation or toxicity was responsible for several drug failures in clinical trials.13−15 Consequently, reducing AO metabolism is crucial for drug development. The strategy to diminish AO oxidation comprises introduction of substitution on the © XXXX American Chemical Society

Figure 1. JNJ38877605 and its AO metabolites.

metabolic site, alternation of the heterocycles that vulnerable to AO enzyme, or incorporation of hindrance close to the oxidation site.16−19 Besides, deuterium replacement in the AO metabolic site will maintain the biological properties of the protic predecessor based on the similar van der Waals volume of C−H and C−D bond and might partly block AO oxidation because of deuterium kinetic isotope effect.20−23 The approach to block the AO oxidation of JNJ38877605 is to alternate the quinoline scaffold that is vulnerable to AO or Received: July 18, 2018 Published: October 4, 2018 A

DOI: 10.1021/acs.chemrestox.8b00191 Chem. Res. Toxicol. XXXX, XXX, XXX−XXX

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Chemical Research in Toxicology

Cell Proliferation Assessment. MKN-45 (human gastric cancer) or EBC-1 (human nonsmall cell lung cancer) cells were seeded in 96-well tissue culture plates and maintained for 1 day. Then the cells were incubated with multiple concentrations of compound 3 or JNJ38877605 for 72 h. Cell proliferation assays were then conducted using sulforhodamine B (SRB, from Sigma-Aldrich, St Louis, MO, USA) method. The IC50 values were calculated by concentration− response curve fitting via the four-parameter method. Each reagent and concentration was tested at least in triplicate during each experiment, and each experiment was performed at least twice. In Vitro Monkey Liver S9 Incubations. Monkey liver S9 fraction (XenoTech, USA) incubations were conducted in potassium phosphate buffer (PBS, 100 mM, pH 7.4) at 37 °C in a total volume of 200 μL. JNJ38877605 or 3 was dissolved in DMSO to prepare a substrate solution of 3 mM. The final concentration of DMSO in the incubation mixture was 0.1% (v/v). Reaction mixtures of PBS (with or without NADPH (2.0 mM)) and 3 μM of substrate (JNJ38877605 or 3) were pre-incubated at 37 °C for 3 min, then the reactions were initiated as the addition of 2.0 mg/mL monkey liver S9 fraction protein. The concentrations of each components were the final concentration. Reactions were terminated by addition an equal volume of ice-cold acetonitrile after incubation for 60 min. Control experiments were generated with inactivated S9 protein. Each incubation was performed in duplicate. Pharmacokinetic and Metabolic Profiles Obtained in Cynomolgus Monkeys. Compound 3 or JNJ38877605 was po. administrated (10 mg/kg) to cynomolgus monkeys by nasal gavage as a formulation containing 0.1% Tween 80 and 0.5% CMC-Na. Blood samples were venously collected from the extremities at 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 h following oral dosing. Serum samples were collected by centrifugation of blood samples, and they were stored at −70 °C. Urine samples of 0−8 h and 8−24 h after po. administration were collected and stored at −70 °C. Pharmacokinetic data were obtained from the analysis of serum samples by HPLC-coupled tandem mass spectrometry (LC-MS/MS). Metabolic profiles were gained from detection of the serum and plasma samples by UPLC-Q/TOF-MS method. All animal experiments were performed according to the institutional ethical guidelines on animal care and approved by the Institute Animal Care and Use Committee at Shanghai Institute of Materia Medica (approval no. 2014-08-RJ-87). UPLC-Q/TOF MS Analysis. Incubation samples were vortex-mixed and centrifuged at 14000g for 5 min. The supernatant was separated and evaporated under nitrogen atmosphere at 40 °C, and the residue was dissolved in 80 μL of mixed acetonitrile/water (10/90, v/v) solvent to yield the test solution. A 10 μL of the test solution was injected for the UPLC-Q/TOF MS analysis. The chromatographic separation of the substrates and their metabolites was achieved on UPLC system (Acquity, Waters, Milford, MA, USA): Column, ACQUITY BEH C18 1.8 μm, 100 mm × 2.1 mm i.d.; solvent system, water containing 0.1% formic acid (A) and acetonitrile containing 0.1% formic acid (B), gradient elution; flow rate, 0.4 mL/min; column temperature, 45 °C. The eluted fractions were monitored by UV detection at 314 nm. Q-TOF MS analysis was conducted on a Synapt Q-TOF high-resolution mass spectrometer (Waters) in positive ion electrospray (ESI) mode. The desolvation gas was 700 L/h at 400 °C, and the source temperature was 120 °C. The capillary voltage was set at 3500 V. MSE scans performed with two independent collision energies. At low collision energy, the transfer and trap collision energies were 4 and 6 eV, respectively. At high collision energy, the transfer collision energy was 25 eV, and trap collision energy ranged from 20 to 30 eV. Data from m/z 80 to 1000 were collected and corrected by a 400 ng/mL internal reference (leucine enkephalin, m/z 556.2771) solution infused at 5 μL/min. In Vivo Antitumor Evaluation. Nude mice were housed and maintained under specific-pathogen free conditions. Animal procedures were approved by the Institutional Animal Care and Use Committee at Shanghai Institute of Materia Medica (approval No. 2014-03-DJ-13). The EBC-1 tumor cells at a density of 5−10 × 106 per 200 μL were injected subcutaneously (sc.) into the right flank of nude mice and then allowed to grow to 700−800 mm3, which was defined as a welldeveloped tumor. Subsequently, the well-developed tumors were cut into 1.5 mm3 fragments and transplanted sc. by a trocar into the right

introduce a substitution on the metabolic site. Replacement of the quinoline scaffold with an imidazo[1,2-a]pyridine maintained the canonical hydrogen bond with Met1160 as well as avoided AO metabolism, leading to the discovery of Volitinib,24,25 a potent c-Met inhibitor in phase III clinical trial. Since substitution on the 2-position of quinoline ring (AO metabolic site) would interfere with the key hydrogen-bonding interaction between quinoline nitrogen atom and Met1160 and lead to decreased c-Met potency, rare optimization on the position was carried out.26−28 Fluorination on the AO metabolic site of JNJ38877605 is capable of hindering AO metabolism, while the fluorine atom situated on quinoline 2-postion will impair the key hydrogen bond26 between the quinoline nitrogen atom and Met 1160, which leads to weakened biological c-Met activity. Therefore, fluorine replacement as the approach to inhibit AO metabolism for JNJ38877605 is infeasible. We envisioned that deuterium replacement on the AO metabolic site of JNJ38877605 could block AO metabolism and reduce the toxic metabolites, leading to lowering its renal toxicity. Thus, we synthesized the deuterated JNJ38877605 (3) and evaluated its metabolic, pharmacokinetic, and antitumor properties. In this article we report that deuterium replacement on AO metabolic site of JNJ38877605 significantly improves its AO oxidation, oral exposure, as well as in vivo antitumor efficacy.

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EXPERIMENTAL PROCEDURES

Chemistry. Preparation of compounds 1, 2a, 3, and 10 is described in the Supporting Information. All reagents and solvents were purchased from commercial sources and used as received. 1H NMR and 13C NMR were generated in DMSO-d6 or CDCl3 on Bruker 300, 400, or 600 NMR spectrometers. High-resolution mass spectra (HRMS) were recorded on Finnigan/MAT95 spectrometer (EI) or Waters Q-Tof Ultima apparatus (ESI). HPLC conditions were as follows: column, Agilent Eclipse Plus C18 5 μM, 4.6 mm × 250 mm; solvent system, MeCN/H2O; flow rate, 1.0 mL/min; UV detection, 254 nm; injection volume, 5 μL; temperature, 35 °C. All the assayed compounds displayed a purity of >95% as confirmed by HPLC. Deuterium isotopic enrichment of compound 3 confirmed by NMR spectroscopy was over 98.0%. c-Met Kinase ELISA Assay. The enzymatic c-Met activity of compound 3 or JNJ38877605 was determined by enzyme-linked immunosorbent assays (ELISAs) using purified recombinant protein. Briefly, 20 μg/mL poly(Glu,Tyr)4:1 (Sigma, St Louis, MO, USA) was precoated in 96-well plates as a substrate. A 50 μL aliquot of 10 μmol/L ATP solution diluted kinase reaction buffer (50 mmol/L HEPES [pH 7.4], 50 mmol/L MgCl2, 0.5 mmol/L MnCl2, 0.2 mmol/L Na3VO4, and 1 mmol/L DTT) was added to each well; 1 μL of various concentrations of 3 or JNJ38877605 diluted in 1% DMSO (v/v) (Sigma, St Louis, MO, USA) were then added to each reaction well. DMSO (1%, v/v) was used as the negative control. The kinase reaction was initiated by the addition of 49 μL kinase reaction buffer diluted c-Met protein. After incubation for 60 min at 37 °C, the plate was washed three times with phosphate-buffered saline (PBS) containing 0.1% Tween 20 (T-PBS). Antiphosphotyrosine (PY99) antibody (100 μL; 1:500, diluted in 5 mg/mL BSA T-PBS) was then added. After an incubation of 30 min at 37 °C, the plate was washed three times, and then 100 μL horseradish peroxidase-conjugated goat antimouse IgG (1:2000, diluted in 5 mg/mL BSA T-PBS) was added. The plate was then incubated at 37 °C for 30 min and washed 3 times. A 100 μL aliquot of a solution containing 0.03% H2O2 and 2 mg/mL o-phenylenediamine in 0.1 mol/L citrate buffer (pH 5.5) was added. The reaction was terminated with color changing by the addition of 50 μL of 2 M H2SO4 to each well, and the plate was detected on a multiwell spectrophotometer (SpectraMAX 190, Molecular Devices, Palo Alto, CA, USA) at 490 nm. Inhibition rate (%) was calculated from the following equation: [1 − (A490/A490 control)] × 100%. The IC50 values were calculated from the inhibition curves in two separate experiments. B

DOI: 10.1021/acs.chemrestox.8b00191 Chem. Res. Toxicol. XXXX, XXX, XXX−XXX

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Chemical Research in Toxicology flank of nude mice. When the tumor volume reached 176 mm3, the mice were randomly assigned into a vehicle control group (n = 12) and treatment groups (n = 6 per group). The control groups were given vehicle alone, and the treatment groups received 3 or JNJ38877605 at the dosage of 5 mg/kg via oral administration twice daily for 3 weeks. The sizes of the tumors were measured twice per week using microcaliper. Tumor volume (TV) was calculated as TV = (length × width2)/2, and the individual relative tumor volume (RTV) was calculated as follows: RTV = Vt/V0, where Vt is the volume on each day, and V0 is the volume at the beginning of the treatment. RTV was shown on indicated days as the median RTV ± SE indicated for groups of mice. Percent (%) inhibition values (TGI) were measured on the final day of study for drug-treated compared with vehicle-treated mice and are calculated as 100 × {1 − [(Vtreated final day − Vtreated day 0)/(Vvehicle final day − Vvehicle day 0)]}. Significant differences between the treated versus the vehicle groups (P ≤ 0.05) were determined by Student’s t test.

oxidized by mCPBA to yield 10 as the quinoline N-oxidation metabolite M2-1. Compound 10 was treated with 4-toluene sulfonyl chloride and potassium carbonate to generate the AO metabolite 2a. Deuteration on the AO Metabolic Site of JNJ38877605 Caused Little Impact on Both Enzymatic and Cellular c-Met Activities. Deuterated JNJ38877605 (3) was assayed enzymatic and cellular c-Met activities. Compared with JNJ38877605, compound 3 displayed slightly decreased enzymatic c-Met activities, as well as c-Met-mediated (EBC-1 and MKN45) cellular activities (Table 1), which demonstrated our hypothesis that deuterium labeling caused little impact on c-Met potency. Table 1. Enzymatic and Cellular c-Met Activities of JNJ38877605 and Compound 3a

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RESULTS Synthesis. Preparation of JNJ38877605 (1) and deuterated JNJ38877605 (3) is depicted in Scheme 1. The quinoline 2-position

IC50 (nM)

Scheme 1. Synthesis of 1 and 3a

a

compd.

c-Met

EBC-1

MKN45

3 JNJ38877605

2.6 ± 0.2 1.7 ± 0.1

17.0 ± 1.2 8.4 ± 0.1

25.0 ± 1.0 18.6 ± 1.1

Values are the mean ± SD of two independent assays.

In Vitro Monkey Liver S9 Fraction Incubation of Compound 3. To evaluate the AO metabolic profile of compound 3 in vitro, monkey liver S9 fraction incubations were carried out, using JNJ38877605 as comparison. As Figure 2 and Table S1 illustrate, three metabolites of JNJ38877605 (M1, M2-1, and M2-2) or compound 3 (D-M1, D-M2-1, D-M2-2) were detected by UPLC-Q/TOF MS. The proposed metabolic pathways are depicted in Figure 3. Metabolite M2-2 (D-M2-2) was not NADPH-dependent, which indicated that it was catalyzed by aldehyde oxidase. The structure of the main metabolites M2-1/ M2-2 were identified by matching the UPLC-Q/TOF MS fragments of M2-1/M2-2 with the mass fragments of the synthesized compounds 10/2a (Figure S1). Compared with JNJ38877605, compound 3 displayed significantly reduced AO metabolite D-M2-2 (Table S1, Figure 2), suggesting that deuterium labeling could partly block in vitro AO oxidation. Metabolic and Pharmacokinetic Properties of Compound 3. After po. administration of 3 or JNJ38877605 at a dosage of 10 mg/kg to cynomolgus monkeys, the metabolic and pharmacokinetic properties were investigated. As depicted in Table S2, 11 metabolites of compound 3 (D-M1, D-M2-1, M2-2, D-M3-1, M3-2, D-M4, M5, D-M3-3, D-M6, M7, and D-M8) and seven metabolites (M1, M2-1, M2-2, M3-1, M3-2, M4, and M5) of JNJ38877605 were detected in the plasma and the urine of cynomolgus monkeys by UPLC-Q/TOF MS. The proposed metabolic pathways of compound 3 and JNJ38877605 are exhibited in Figures S2 and S3 in the Supporting Information. The metabolite D-M6 (glucuronidation of D-M1) is the exclusive metabolite of the deuterated JNJ38877605. Compared with JNJ38877605, its deuterated counterpart displayed diminished renal toxic metabolites (M2-2, M3-2) in the plasma (Table 2), indicating that deuteration partly blocked AO oxidation in vivo. Moreover, compound 3 displayed a 1.88-fold AUC and a 1.56-fold Cmax of JNJ38877605 (Table 3), suggesting that deuterated JNJ38877605 displayed better oral exposure than JNJ38877605. Compound 3 Exhibited Better in Vivo Antitumor Efficacy Than JNJ38877605. To investigate whether the improved oral exposure of deuterated JNJ38877605 would advance the antitumor efficacy, compound 3 was evaluated the in vivo antitumor activity in EBC-1 (human nonsmall cell lung cancer)

a Reagents and conditions: (a) NaOtBu, D2O, 100 °C; (b) PCl3, CHCl3, reflux; (c) CuI, NaI, N,N′-dimethylethylenediamine, dioxane, reflux; (d) (i) ethyl bromodifluoroacetate, Cu, DMSO, 60 °C; (ii) hydrazine hydrate, MeOH; (e) 1-methoxy-2-propanol, 120 °C.

deuterated material 5 was synthesized from 6-bromoquinoline-1oxide (4) via deuterium atom exchange. Intermediate 6 was prepared by reduction of 5, which then transformed to 7 by iodization. Compound 7 was coupled with ethyl bromodifluoroacetate under the participation of copper powder, then the reaction mixture was treated with hydrazine hydrate to yield 8b. Compound 3 (or 1) was prepared by heating the mixture of acetohydrazide 8b (or 8a) and chloride 9 in 1-methoxy-2-propanol at a temperature of 120 °C. Synthesis of the metabolites M2-1 (10) and M2-2 (2a) is exhibited in Scheme 2. Compound 1 was Scheme 2. Synthesis of 10 (M2-1) and 2a (M2-2)a

a

Reagents and conditions: (a) mCPBA, MeOH, DCM; (b) 4-toluene sulfonyl chloride, K2CO3, H2O, THF. C

DOI: 10.1021/acs.chemrestox.8b00191 Chem. Res. Toxicol. XXXX, XXX, XXX−XXX

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Chemical Research in Toxicology

Figure 2. Metabolic profiles of JNJ38877605 and compound 3 by in vitro monkey liver S9 fraction incubations, as detected by UPLC-Q/TOF MS. (A) JNJ38877605 incubated with NADPH. (B) JNJ38877605 incubated without NADPH. (C) Compound 3 incubated with NADPH. (D) Compound 3 incubated without NADPH.

Figure 3. Proposed metabolic pathways of JNJ38877605 and compound 3 by in vitro monkey liver S9 fraction incubations.

Table 2. UPLC-UV Peak Areas of Main Metabolites of JNJ38877605 and Compound 3 in the Plasma of Cynomolgus Monkeys after po. Administration (10 mg/kg) UV peak area compd.

JNJ38877605

3

no.

description

ret (min)

plasma (2 h)

plasma (12 h)

M0 M2-1 M2-2 M3-2 D-M0 D-M2-1 M2-2 M3-2 D-M6

parent N-oxidation of qunoline hydroxylation of quinoline N-demethylation of M2-2 parent qunoline N-oxidation quinoline hydroxylation N-demethylation of M2-2 glucuronidation of D-M1

7.13 5.55 5.98 5.24 7.14 5.55 5.99 5.24 4.45

333.0 58.2 159.0 86.0 649.0 101.0 84.7 31.4 42.2

128.0 36.1 52.4 52.2 374.0 105.0 56.6 30.0 23.3

nude mice xenografts. After a dosage of 5 mg/kg po. administration for 3 weeks, compound 3 exhibited a 90.4% TGI compared with an 83.8% TGI of JNJ38877605 in the tumor-bearing nude

mice (P < 0.05), and it was well tolerated with no observatory weight loss (data not shown), which suggested that deuterium replacement improved the in vivo antitumor efficacy (Figure 4). D

DOI: 10.1021/acs.chemrestox.8b00191 Chem. Res. Toxicol. XXXX, XXX, XXX−XXX

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Chemical Research in Toxicology ORCID

Table 3. Pharmacokinetic Profiles of 3 and JNJ38877605 in Monkeysa compd.

Tmax (h)

Cmax (ng/mL)

AUC0‑∞ (h·ng/mL)

T1/2 (h)

3 JNJ38877605

2.0 1.5

1948 1252

37067 19749

14.2 18.2

Wenhu Duan: 0000-0002-5084-6026 Author Contributions §

These authors contributed equally to this work.

Notes

The authors declare no competing financial interest.

a

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Experiments were carried out in male cynomolgus monkeys (n = 2); dose: po. 10 mg/kg (0.1% Tween 80 and 0.5% CMC-Na).

ACKNOWLEDGMENTS We thank Shanghai Sailing Program (no. 17YF1423300), the Youth Innovation Promotion Association of CAS (no. 2018324), Major Projects in National Science and Technology of China (nos. 2018ZX09711002-011-016 and 2018ZX09711002-004-013), and the National Natural Science Foundation of China (nos. 81573271 and 21702220) for their financial support.

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ABBREVIATIONS HGFR, hepatocyte growth factor receptor; AO, aldehyde oxidase; MKN-45, human gastric cancer cells; EBC-1, human nonsmall cell lung cancer cells; IC50, half-maximal inhibitory concentration; mCPBA, 3-chloroperbenzoic acid; PCl3, phosphorus trichloride; CuI, copper iodide; NaI, sodium, iodide; K2CO3, potassium carbonate; MgCl2, magnesium chloride; MnCl2, manganese chloride; Na3VO4, sodium vanadate; CMCNa, sodium carboxymethylcellulose

Figure 4. Compound 3 displayed better in vivo antitumor efficacy than JNJ38877605 in EBC-1 xenografts. The tumor-bearing mice were administrated (po.) 3 or JNJ38877605 twice daily for 3 weeks. Mean relative tumor volume ± SE was shown (n = 6 in treated group, n = 12 in vehicle group). ***P < 0.001 vs vehicle group, *P < 0.05 compound 3 vs JNJ38877605 group, determined by Student’s t test.

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DISCUSSION Compound 3 was prepared as a version of deuterated JNJ38877605 on the AO metabolic site. Monkey liver S9 fraction incubation of 3 revealed that the renal toxic metabolite M2-2 remarkably reduced, which demonstrated that deuteration has partly blocked AO oxidation in vitro. After po. administration at a dosage of 10 mg/kg to cynomolgus monkeys, compound 3 displayed diminished AO metabolites M2-2 and M3-2 in the plasma as well as 1.88-fold AUC and 1.56-fold Cmax compared with JNJ38877605. In the plasma and the urine of the po. administrated cynomolgus monkeys, 11 metabolites of compound 3 were detected. Among them, the glucuronidation metabolite D-M6 was the exclusive metabolite of compound 3. Moreover, after a dosage of 5 mg/kg oral administration twice daily to the EBC-1 tumor-bearing nude mice for 3 weeks, compound 3 manifested a better antitumor activity than JNJ38877605, with TGI of 90.4% vs 83.8%. In summary, deuterium replacement of JNJ38877605 improved its AO metabolism, oral exposure, as well as the antitumor potency.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.chemrestox.8b00191. Synthetic procedures and analytical data for compounds 1, 2a, 3, and 10 and supplementary Figures and Tables (PDF)

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REFERENCES

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. Phone: +86-21-50806600-2413. *E-mail: [email protected]. Phone: +86-21-50806032. E

DOI: 10.1021/acs.chemrestox.8b00191 Chem. Res. Toxicol. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.chemrestox.8b00191 Chem. Res. Toxicol. XXXX, XXX, XXX−XXX