compound az2  (AstraZeneca ltd)

Journal: British Journal of Pharmacology

Article Title: Neutrophil maturation rate determines the effects of dipeptidyl peptidase 1 inhibition on neutrophil serine protease activity

doi: 10.1111/bph.13515

Figure Lengend Snippet: Time course for onset of inhibition of NE and PR3 activities in blood and bone marrow after oral administration of the DPP1 inhibitor AZ1 to rats, (a–d) NE and PR3 activities in bone marrow and blood in onset 1, (e and f) NE and PR3 activities in blood in onset 2. The horizontal lines represent the median value in each group, the percent inhibition is the median value in the respective group compared with the median value in the vehicle‐treated group, the dotted line represents the buffer signal, V = vehicle and BM = bone marrow.

Article Snippet: The DPP1 inhibitor compounds AZ1 ((S)‐N‐((S)‐1‐cyano‐2‐(4′‐cyanobiphenyl‐4‐yl)ethyl)piperidine‐2‐carboxamide) and AZ2 ((S)‐4‐amino‐N‐(1‐cyano‐2‐(4′‐cyanobiphenyl‐4‐yl)ethyl)tetrahydro‐2H‐pyran‐4‐carboxamide) were supplied by AstraZeneca R&D (Table ).

Techniques: Inhibition

Journal: British Journal of Pharmacology

Article Title: Neutrophil maturation rate determines the effects of dipeptidyl peptidase 1 inhibition on neutrophil serine protease activity

doi: 10.1111/bph.13515

Figure Lengend Snippet: Time course for recovery of (a) NE, (b) PR3 and (c) CatG activities in bone marrow in AZ2‐treated and vehicle‐treated (control) rats. The DPP1 inhibitor AZ2 or vehicle control was administered orally twice daily for 8 days, the first dose in the morning and the second 8 h later. The rats were killed at 9 day intervals on day 0, 9 or 18 after the end of the treatment. The horizontal line represents the median value in each group, the percent inhibition is the median value in the respective group compared with the median value in the matched vehicle‐treated group, the dotted line represents the buffer signal, V = vehicle and BM = bone marrow.

Article Snippet: The DPP1 inhibitor compounds AZ1 ((S)‐N‐((S)‐1‐cyano‐2‐(4′‐cyanobiphenyl‐4‐yl)ethyl)piperidine‐2‐carboxamide) and AZ2 ((S)‐4‐amino‐N‐(1‐cyano‐2‐(4′‐cyanobiphenyl‐4‐yl)ethyl)tetrahydro‐2H‐pyran‐4‐carboxamide) were supplied by AstraZeneca R&D (Table ).

Techniques: Control, Inhibition

Journal: British Journal of Pharmacology

Article Title: Neutrophil maturation rate determines the effects of dipeptidyl peptidase 1 inhibition on neutrophil serine protease activity

doi: 10.1111/bph.13515

Figure Lengend Snippet: (a) Simulated time course of concentration of AZ1 after an oral dose (3.6 mg·kg −1 ) in rat with markers showing dose‐adjusted observed pharmacokinetic data, 0–8 h. (b) Simulated time course of concentration of AZ1 and fraction of DPP1 inhibition after twice daily oral dose (3.6 mg·kg −1 and 10.7 mg·kg −1 after 8 h) in rat 0–8 days. (c) Best fit to the observed time course of NSP inhibition after oral administration of AZ1 in the onset study. Note: observed CatG inhibition data from the onset study were not included in the fitting.

Article Snippet: The DPP1 inhibitor compounds AZ1 ((S)‐N‐((S)‐1‐cyano‐2‐(4′‐cyanobiphenyl‐4‐yl)ethyl)piperidine‐2‐carboxamide) and AZ2 ((S)‐4‐amino‐N‐(1‐cyano‐2‐(4′‐cyanobiphenyl‐4‐yl)ethyl)tetrahydro‐2H‐pyran‐4‐carboxamide) were supplied by AstraZeneca R&D (Table ).

Techniques: Concentration Assay, Inhibition

Journal: British Journal of Pharmacology

Article Title: Neutrophil maturation rate determines the effects of dipeptidyl peptidase 1 inhibition on neutrophil serine protease activity

doi: 10.1111/bph.13515

Figure Lengend Snippet: (a) Simulated time course of concentration of AZ2 and fraction of DPP1 inhibition after twice daily oral administration (10 mg·kg −1 ) in rat. Markers show exposure data in rats in the recovery study. (b) Best fit to the observed time course of NSP inhibition after oral administration of AZ2 in the recovery study in rat.

Article Snippet: The DPP1 inhibitor compounds AZ1 ((S)‐N‐((S)‐1‐cyano‐2‐(4′‐cyanobiphenyl‐4‐yl)ethyl)piperidine‐2‐carboxamide) and AZ2 ((S)‐4‐amino‐N‐(1‐cyano‐2‐(4′‐cyanobiphenyl‐4‐yl)ethyl)tetrahydro‐2H‐pyran‐4‐carboxamide) were supplied by AstraZeneca R&D (Table ).

Techniques: Concentration Assay, Inhibition

Journal: British Journal of Pharmacology

Article Title: Neutrophil maturation rate determines the effects of dipeptidyl peptidase 1 inhibition on neutrophil serine protease activity

doi: 10.1111/bph.13515

Figure Lengend Snippet: (a) Left‐hand panel shows simulated time course of concentration of AZ2 and fraction of DPP1 inhibition following once daily oral administration in human at a dose that is predicted to give a steady state average concentration of 3 × IC 50 and inhibits DPP1 by 75%. Right‐hand panel shows simulated time course of NSP inhibition in human after oral administration of AZ2. (b) Simulated effect of a missed dose on day 24 (typically after steady state is reached). (c) Simulated recovery of NSP activity following the discontinuation of treatment with AZ2.

Article Snippet: The DPP1 inhibitor compounds AZ1 ((S)‐N‐((S)‐1‐cyano‐2‐(4′‐cyanobiphenyl‐4‐yl)ethyl)piperidine‐2‐carboxamide) and AZ2 ((S)‐4‐amino‐N‐(1‐cyano‐2‐(4′‐cyanobiphenyl‐4‐yl)ethyl)tetrahydro‐2H‐pyran‐4‐carboxamide) were supplied by AstraZeneca R&D (Table ).

Techniques: Concentration Assay, Inhibition, Activity Assay

Journal: British Journal of Pharmacology

Article Title: Neutrophil maturation rate determines the effects of dipeptidyl peptidase 1 inhibition on neutrophil serine protease activity

doi: 10.1111/bph.13515

Figure Lengend Snippet:

Article Snippet: The DPP1 inhibitor compounds AZ1 ((S)‐N‐((S)‐1‐cyano‐2‐(4′‐cyanobiphenyl‐4‐yl)ethyl)piperidine‐2‐carboxamide) and AZ2 ((S)‐4‐amino‐N‐(1‐cyano‐2‐(4′‐cyanobiphenyl‐4‐yl)ethyl)tetrahydro‐2H‐pyran‐4‐carboxamide) were supplied by AstraZeneca R&D (Table ).

Techniques:

Journal: British Journal of Pharmacology

Article Title: Neutrophil maturation rate determines the effects of dipeptidyl peptidase 1 inhibition on neutrophil serine protease activity

doi: 10.1111/bph.13515

Figure Lengend Snippet: Chemical structures of the DPP1 inhibitor compounds AZ1 and AZ2

Article Snippet: The DPP1 inhibitor compounds AZ1 ((S)‐N‐((S)‐1‐cyano‐2‐(4′‐cyanobiphenyl‐4‐yl)ethyl)piperidine‐2‐carboxamide) and AZ2 ((S)‐4‐amino‐N‐(1‐cyano‐2‐(4′‐cyanobiphenyl‐4‐yl)ethyl)tetrahydro‐2H‐pyran‐4‐carboxamide) were supplied by AstraZeneca R&D (Table ).

Techniques:

Journal: British Journal of Pharmacology

Article Title: Neutrophil maturation rate determines the effects of dipeptidyl peptidase 1 inhibition on neutrophil serine protease activity

doi: 10.1111/bph.13515

Figure Lengend Snippet: Parameters employed in the indirect response model

Article Snippet: The DPP1 inhibitor compounds AZ1 ((S)‐N‐((S)‐1‐cyano‐2‐(4′‐cyanobiphenyl‐4‐yl)ethyl)piperidine‐2‐carboxamide) and AZ2 ((S)‐4‐amino‐N‐(1‐cyano‐2‐(4′‐cyanobiphenyl‐4‐yl)ethyl)tetrahydro‐2H‐pyran‐4‐carboxamide) were supplied by AstraZeneca R&D (Table ).

Techniques: