Journal: Journal of Medicinal Chemistry

Article Title: Design, Synthesis, and Biological Evaluation of a Novel Series of 4-Guanidinobenzoate Derivatives as Enteropeptidase Inhibitors with Low Systemic Exposure for the Treatment of Obesity

doi: 10.1021/acs.jmedchem.2c00463

Figure Lengend Snippet: Small-molecule enteropeptidase inhibitors that exert pharmacological effects in DIO mice.

Article Snippet: 10 μL of compound solution was added in 96-well plate (corning), and then, 10 μL of 100 mU/mL human recombinant enteropeptidase (ITSI-Biosciences) solution was added into the plate and incubated at room temperature for 2 h. The concentration of the compound was equal to 10-fold the IC 50 value at 120 min incubation.

Techniques:

Journal: Journal of Medicinal Chemistry

Article Title: Design, Synthesis, and Biological Evaluation of a Novel Series of 4-Guanidinobenzoate Derivatives as Enteropeptidase Inhibitors with Low Systemic Exposure for the Treatment of Obesity

doi: 10.1021/acs.jmedchem.2c00463

Figure Lengend Snippet: Structures of 1a–1c . Human enteropeptidase IC 50(initial) refers to the inhibitory activity of human enteropeptidase after 6 min of incubation with the enzyme, substrate, and compound. Human enteropeptidase IC 50(app) refers to the apparent IC 50 value after 120 min of incubation with the enzyme, substrate, and compound.

Article Snippet: 10 μL of compound solution was added in 96-well plate (corning), and then, 10 μL of 100 mU/mL human recombinant enteropeptidase (ITSI-Biosciences) solution was added into the plate and incubated at room temperature for 2 h. The concentration of the compound was equal to 10-fold the IC 50 value at 120 min incubation.

Techniques: Activity Assay, Incubation

Journal: Journal of Medicinal Chemistry

Article Title: Design, Synthesis, and Biological Evaluation of a Novel Series of 4-Guanidinobenzoate Derivatives as Enteropeptidase Inhibitors with Low Systemic Exposure for the Treatment of Obesity

doi: 10.1021/acs.jmedchem.2c00463

Figure Lengend Snippet: Docking model of 1c with enteropeptidase. The apo form of human enteropeptidase (PDB ID: 4DGJ ) was used as a template. The surface of the catalytic triad (His825, Asp876, and Ser971) is illustrated in cyan.

Article Snippet: 10 μL of compound solution was added in 96-well plate (corning), and then, 10 μL of 100 mU/mL human recombinant enteropeptidase (ITSI-Biosciences) solution was added into the plate and incubated at room temperature for 2 h. The concentration of the compound was equal to 10-fold the IC 50 value at 120 min incubation.

Techniques:

Journal: Journal of Medicinal Chemistry

Article Title: Design, Synthesis, and Biological Evaluation of a Novel Series of 4-Guanidinobenzoate Derivatives as Enteropeptidase Inhibitors with Low Systemic Exposure for the Treatment of Obesity

doi: 10.1021/acs.jmedchem.2c00463

Figure Lengend Snippet: Proposed mechanism for enteropeptidase inhibition by 1c .

Article Snippet: 10 μL of compound solution was added in 96-well plate (corning), and then, 10 μL of 100 mU/mL human recombinant enteropeptidase (ITSI-Biosciences) solution was added into the plate and incubated at room temperature for 2 h. The concentration of the compound was equal to 10-fold the IC 50 value at 120 min incubation.

Techniques: Inhibition

Journal: Journal of Medicinal Chemistry

Article Title: Design, Synthesis, and Biological Evaluation of a Novel Series of 4-Guanidinobenzoate Derivatives as Enteropeptidase Inhibitors with Low Systemic Exposure for the Treatment of Obesity

doi: 10.1021/acs.jmedchem.2c00463

Figure Lengend Snippet: (A) Docking model of 2a with enteropeptidase. The apo form of human enteropeptidase (PDB ID: 4DGJ ) was used as a template. The surface of the catalytic triad is highlighted in cyan. (B) Properties of 2a . (C) Increase in fecal protein output. (D) Plasma exposure of 2a by oral (60 mg/kg) and subcutaneous (10 mg/kg) administration in mice. ###; P ≤ 0.01, vs vehicle using the Aspin–Welch test vs the vehicle.

Article Snippet: 10 μL of compound solution was added in 96-well plate (corning), and then, 10 μL of 100 mU/mL human recombinant enteropeptidase (ITSI-Biosciences) solution was added into the plate and incubated at room temperature for 2 h. The concentration of the compound was equal to 10-fold the IC 50 value at 120 min incubation.

Techniques:

Journal: Journal of Medicinal Chemistry

Article Title: Design, Synthesis, and Biological Evaluation of a Novel Series of 4-Guanidinobenzoate Derivatives as Enteropeptidase Inhibitors with Low Systemic Exposure for the Treatment of Obesity

doi: 10.1021/acs.jmedchem.2c00463

Figure Lengend Snippet: Docking model of 4b with enteropeptidase. The apo form of human enteropeptidase (PDB ID: 4DGJ ) was used as a template. (A) Overall structure. The surface of the catalytic triad is highlighted in cyan. (B) Top view of the S2 site. (C) Replacement of the amide group of 4b with bioisosteres. (D) Superposition of 6a (green) and 6b (magenta) to enteropeptidase-docked 4b (gray) by MOE. (E) Calculation of the charge distribution.

Article Snippet: 10 μL of compound solution was added in 96-well plate (corning), and then, 10 μL of 100 mU/mL human recombinant enteropeptidase (ITSI-Biosciences) solution was added into the plate and incubated at room temperature for 2 h. The concentration of the compound was equal to 10-fold the IC 50 value at 120 min incubation.

Techniques:

Journal: Journal of Medicinal Chemistry

Article Title: Design, Synthesis, and Biological Evaluation of a Novel Series of 4-Guanidinobenzoate Derivatives as Enteropeptidase Inhibitors with Low Systemic Exposure for the Treatment of Obesity

doi: 10.1021/acs.jmedchem.2c00463

Figure Lengend Snippet: Properties of ( S )-5b and 6b . Rat enteropeptidase IC 50(app) refers to the inhibitory activity of rat enteropeptidase after 120 min of incubation of the enzyme, substrate, and compound.

Article Snippet: 10 μL of compound solution was added in 96-well plate (corning), and then, 10 μL of 100 mU/mL human recombinant enteropeptidase (ITSI-Biosciences) solution was added into the plate and incubated at room temperature for 2 h. The concentration of the compound was equal to 10-fold the IC 50 value at 120 min incubation.

Techniques: Activity Assay, Incubation

Journal: Journal of Medicinal Chemistry

Article Title: Design, Synthesis, and Biological Evaluation of a Novel Series of 4-Guanidinobenzoate Derivatives as Enteropeptidase Inhibitors with Low Systemic Exposure for the Treatment of Obesity

doi: 10.1021/acs.jmedchem.2c00463

Figure Lengend Snippet: In Vitro Activities and T 1/2 of 2a and 3a–d

Article Snippet: 10 μL of compound solution was added in 96-well plate (corning), and then, 10 μL of 100 mU/mL human recombinant enteropeptidase (ITSI-Biosciences) solution was added into the plate and incubated at room temperature for 2 h. The concentration of the compound was equal to 10-fold the IC 50 value at 120 min incubation.

Techniques: In Vitro

Journal: Journal of Medicinal Chemistry

Article Title: Design, Synthesis, and Biological Evaluation of a Novel Series of 4-Guanidinobenzoate Derivatives as Enteropeptidase Inhibitors with Low Systemic Exposure for the Treatment of Obesity

doi: 10.1021/acs.jmedchem.2c00463

Figure Lengend Snippet: In Vitro and In Vivo Activities of 4a–c

Article Snippet: 10 μL of compound solution was added in 96-well plate (corning), and then, 10 μL of 100 mU/mL human recombinant enteropeptidase (ITSI-Biosciences) solution was added into the plate and incubated at room temperature for 2 h. The concentration of the compound was equal to 10-fold the IC 50 value at 120 min incubation.

Techniques: In Vitro, In Vivo

Journal: Journal of Medicinal Chemistry

Article Title: Design, Synthesis, and Biological Evaluation of a Novel Series of 4-Guanidinobenzoate Derivatives as Enteropeptidase Inhibitors with Low Systemic Exposure for the Treatment of Obesity

doi: 10.1021/acs.jmedchem.2c00463

Figure Lengend Snippet: In Vitro and In Vivo Activities of 5a , ( R )-5b , and ( S )-5b

Article Snippet: 10 μL of compound solution was added in 96-well plate (corning), and then, 10 μL of 100 mU/mL human recombinant enteropeptidase (ITSI-Biosciences) solution was added into the plate and incubated at room temperature for 2 h. The concentration of the compound was equal to 10-fold the IC 50 value at 120 min incubation.

Techniques: In Vitro, In Vivo

Journal: Journal of Medicinal Chemistry

Article Title: Design, Synthesis, and Biological Evaluation of a Novel Series of 4-Guanidinobenzoate Derivatives as Enteropeptidase Inhibitors with Low Systemic Exposure for the Treatment of Obesity

doi: 10.1021/acs.jmedchem.2c00463

Figure Lengend Snippet: In Vitro and In Vivo Activities of 6b and 6c

Article Snippet: 10 μL of compound solution was added in 96-well plate (corning), and then, 10 μL of 100 mU/mL human recombinant enteropeptidase (ITSI-Biosciences) solution was added into the plate and incubated at room temperature for 2 h. The concentration of the compound was equal to 10-fold the IC 50 value at 120 min incubation.

Techniques: In Vitro, In Vivo