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Pernilla Glader - One of the best experts on this subject based on the ideXlab platform.
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discovery of the oral Leukotriene C4 synthase inhibitor 1s 2s 2 5 5 chloro 2 4 difluorophenyl 2 fluoro 2 methylpropyl amino 3 methoxypyrazin 2 yl carbonyl cyclopropanecarboxylic acid azd9898 as a new treatment for asthma
Journal of Medicinal Chemistry, 2019Co-Authors: Magnus Munck Af Rosenschöld, Petra Johannesson, Antonios Nikitidis, Christian Tyrchan, Hui-fang Chang, Robert Ronn, Dave Chapman, Victoria Ullah, Grigorios Nikitidis, Pernilla GladerAbstract:While bronchodilators and inhaled corticosteroids are the mainstay of asthma treatment, up to 50% of asthmatics remain uncontrolled. Many studies show that the cysteinyl Leukotriene cascade remains highly activated in some asthmatics, even those on high-dose inhaled or oral corticosteroids. Hence, inhibition of the Leukotriene C4 synthase (LTC4S) enzyme could provide a new and differentiated core treatment for patients with a highly activated cysteinyl Leukotriene cascade. Starting from a screening hit (3), a program to discover oral inhibitors of LTC4S led to (1S,2S)-2-({5-[(5-chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid (AZD9898) (36), a picomolar LTC4S inhibitor (IC50 = 0.28 nM) with high lipophilic ligand efficiency (LLE = 8.5), which displays nanomolar potency in cells (peripheral blood mononuclear cell, IC50,free = 6.2 nM) and good in vivo pharmacodynamics in a calcium ionophore-stimulated rat model after oral dosing (in vivo, I...
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discovery of the oral Leukotriene C4 synthase inhibitor 1s 2s 2 5 5 chloro 2 4 difluorophenyl 2 fluoro 2 methylpropyl amino 3 methoxypyrazin 2 yl carbonyl cyclopropanecarboxylic acid azd9898 as a new treatment for asthma
Journal of Medicinal Chemistry, 2019Co-Authors: Magnus Munck Af Rosenschöld, Petra Johannesson, Antonios Nikitidis, Christian Tyrchan, Hui-fang Chang, Robert Ronn, Dave Chapman, Victoria Ullah, Grigorios Nikitidis, Pernilla GladerAbstract:While bronchodilators and inhaled corticosteroids are the mainstay of asthma treatment, up to 50% of asthmatics remain uncontrolled. Many studies show that the cysteinyl Leukotriene cascade remains highly activated in some asthmatics, even those on high-dose inhaled or oral corticosteroids. Hence, inhibition of the Leukotriene C4 synthase (LTC4S) enzyme could provide a new and differentiated core treatment for patients with a highly activated cysteinyl Leukotriene cascade. Starting from a screening hit (3), a program to discover oral inhibitors of LTC4S led to (1S,2S)-2-({5-[(5-chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid (AZD9898) (36), a picomolar LTC4S inhibitor (IC50 = 0.28 nM) with high lipophilic ligand efficiency (LLE = 8.5), which displays nanomolar potency in cells (peripheral blood mononuclear cell, IC50,free = 6.2 nM) and good in vivo pharmacodynamics in a calcium ionophore-stimulated rat model after oral dosing (in vivo, IC50,free = 34 nM). Compound 36 mitigates the GABA binding, hepatic toxicity signal, and in vivo toxicology findings of an early lead compound 7 with a human dose predicted to be 30 mg once daily.
Magnus Munck Af Rosenschöld - One of the best experts on this subject based on the ideXlab platform.
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discovery of the oral Leukotriene C4 synthase inhibitor 1s 2s 2 5 5 chloro 2 4 difluorophenyl 2 fluoro 2 methylpropyl amino 3 methoxypyrazin 2 yl carbonyl cyclopropanecarboxylic acid azd9898 as a new treatment for asthma
Journal of Medicinal Chemistry, 2019Co-Authors: Magnus Munck Af Rosenschöld, Petra Johannesson, Antonios Nikitidis, Christian Tyrchan, Hui-fang Chang, Robert Ronn, Dave Chapman, Victoria Ullah, Grigorios Nikitidis, Pernilla GladerAbstract:While bronchodilators and inhaled corticosteroids are the mainstay of asthma treatment, up to 50% of asthmatics remain uncontrolled. Many studies show that the cysteinyl Leukotriene cascade remains highly activated in some asthmatics, even those on high-dose inhaled or oral corticosteroids. Hence, inhibition of the Leukotriene C4 synthase (LTC4S) enzyme could provide a new and differentiated core treatment for patients with a highly activated cysteinyl Leukotriene cascade. Starting from a screening hit (3), a program to discover oral inhibitors of LTC4S led to (1S,2S)-2-({5-[(5-chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid (AZD9898) (36), a picomolar LTC4S inhibitor (IC50 = 0.28 nM) with high lipophilic ligand efficiency (LLE = 8.5), which displays nanomolar potency in cells (peripheral blood mononuclear cell, IC50,free = 6.2 nM) and good in vivo pharmacodynamics in a calcium ionophore-stimulated rat model after oral dosing (in vivo, I...
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discovery of the oral Leukotriene C4 synthase inhibitor 1s 2s 2 5 5 chloro 2 4 difluorophenyl 2 fluoro 2 methylpropyl amino 3 methoxypyrazin 2 yl carbonyl cyclopropanecarboxylic acid azd9898 as a new treatment for asthma
Journal of Medicinal Chemistry, 2019Co-Authors: Magnus Munck Af Rosenschöld, Petra Johannesson, Antonios Nikitidis, Christian Tyrchan, Hui-fang Chang, Robert Ronn, Dave Chapman, Victoria Ullah, Grigorios Nikitidis, Pernilla GladerAbstract:While bronchodilators and inhaled corticosteroids are the mainstay of asthma treatment, up to 50% of asthmatics remain uncontrolled. Many studies show that the cysteinyl Leukotriene cascade remains highly activated in some asthmatics, even those on high-dose inhaled or oral corticosteroids. Hence, inhibition of the Leukotriene C4 synthase (LTC4S) enzyme could provide a new and differentiated core treatment for patients with a highly activated cysteinyl Leukotriene cascade. Starting from a screening hit (3), a program to discover oral inhibitors of LTC4S led to (1S,2S)-2-({5-[(5-chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid (AZD9898) (36), a picomolar LTC4S inhibitor (IC50 = 0.28 nM) with high lipophilic ligand efficiency (LLE = 8.5), which displays nanomolar potency in cells (peripheral blood mononuclear cell, IC50,free = 6.2 nM) and good in vivo pharmacodynamics in a calcium ionophore-stimulated rat model after oral dosing (in vivo, IC50,free = 34 nM). Compound 36 mitigates the GABA binding, hepatic toxicity signal, and in vivo toxicology findings of an early lead compound 7 with a human dose predicted to be 30 mg once daily.
Petra Johannesson - One of the best experts on this subject based on the ideXlab platform.
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discovery of the oral Leukotriene C4 synthase inhibitor 1s 2s 2 5 5 chloro 2 4 difluorophenyl 2 fluoro 2 methylpropyl amino 3 methoxypyrazin 2 yl carbonyl cyclopropanecarboxylic acid azd9898 as a new treatment for asthma
Journal of Medicinal Chemistry, 2019Co-Authors: Magnus Munck Af Rosenschöld, Petra Johannesson, Antonios Nikitidis, Christian Tyrchan, Hui-fang Chang, Robert Ronn, Dave Chapman, Victoria Ullah, Grigorios Nikitidis, Pernilla GladerAbstract:While bronchodilators and inhaled corticosteroids are the mainstay of asthma treatment, up to 50% of asthmatics remain uncontrolled. Many studies show that the cysteinyl Leukotriene cascade remains highly activated in some asthmatics, even those on high-dose inhaled or oral corticosteroids. Hence, inhibition of the Leukotriene C4 synthase (LTC4S) enzyme could provide a new and differentiated core treatment for patients with a highly activated cysteinyl Leukotriene cascade. Starting from a screening hit (3), a program to discover oral inhibitors of LTC4S led to (1S,2S)-2-({5-[(5-chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid (AZD9898) (36), a picomolar LTC4S inhibitor (IC50 = 0.28 nM) with high lipophilic ligand efficiency (LLE = 8.5), which displays nanomolar potency in cells (peripheral blood mononuclear cell, IC50,free = 6.2 nM) and good in vivo pharmacodynamics in a calcium ionophore-stimulated rat model after oral dosing (in vivo, I...
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discovery of the oral Leukotriene C4 synthase inhibitor 1s 2s 2 5 5 chloro 2 4 difluorophenyl 2 fluoro 2 methylpropyl amino 3 methoxypyrazin 2 yl carbonyl cyclopropanecarboxylic acid azd9898 as a new treatment for asthma
Journal of Medicinal Chemistry, 2019Co-Authors: Magnus Munck Af Rosenschöld, Petra Johannesson, Antonios Nikitidis, Christian Tyrchan, Hui-fang Chang, Robert Ronn, Dave Chapman, Victoria Ullah, Grigorios Nikitidis, Pernilla GladerAbstract:While bronchodilators and inhaled corticosteroids are the mainstay of asthma treatment, up to 50% of asthmatics remain uncontrolled. Many studies show that the cysteinyl Leukotriene cascade remains highly activated in some asthmatics, even those on high-dose inhaled or oral corticosteroids. Hence, inhibition of the Leukotriene C4 synthase (LTC4S) enzyme could provide a new and differentiated core treatment for patients with a highly activated cysteinyl Leukotriene cascade. Starting from a screening hit (3), a program to discover oral inhibitors of LTC4S led to (1S,2S)-2-({5-[(5-chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid (AZD9898) (36), a picomolar LTC4S inhibitor (IC50 = 0.28 nM) with high lipophilic ligand efficiency (LLE = 8.5), which displays nanomolar potency in cells (peripheral blood mononuclear cell, IC50,free = 6.2 nM) and good in vivo pharmacodynamics in a calcium ionophore-stimulated rat model after oral dosing (in vivo, IC50,free = 34 nM). Compound 36 mitigates the GABA binding, hepatic toxicity signal, and in vivo toxicology findings of an early lead compound 7 with a human dose predicted to be 30 mg once daily.
Christian Tyrchan - One of the best experts on this subject based on the ideXlab platform.
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discovery of the oral Leukotriene C4 synthase inhibitor 1s 2s 2 5 5 chloro 2 4 difluorophenyl 2 fluoro 2 methylpropyl amino 3 methoxypyrazin 2 yl carbonyl cyclopropanecarboxylic acid azd9898 as a new treatment for asthma
Journal of Medicinal Chemistry, 2019Co-Authors: Magnus Munck Af Rosenschöld, Petra Johannesson, Antonios Nikitidis, Christian Tyrchan, Hui-fang Chang, Robert Ronn, Dave Chapman, Victoria Ullah, Grigorios Nikitidis, Pernilla GladerAbstract:While bronchodilators and inhaled corticosteroids are the mainstay of asthma treatment, up to 50% of asthmatics remain uncontrolled. Many studies show that the cysteinyl Leukotriene cascade remains highly activated in some asthmatics, even those on high-dose inhaled or oral corticosteroids. Hence, inhibition of the Leukotriene C4 synthase (LTC4S) enzyme could provide a new and differentiated core treatment for patients with a highly activated cysteinyl Leukotriene cascade. Starting from a screening hit (3), a program to discover oral inhibitors of LTC4S led to (1S,2S)-2-({5-[(5-chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid (AZD9898) (36), a picomolar LTC4S inhibitor (IC50 = 0.28 nM) with high lipophilic ligand efficiency (LLE = 8.5), which displays nanomolar potency in cells (peripheral blood mononuclear cell, IC50,free = 6.2 nM) and good in vivo pharmacodynamics in a calcium ionophore-stimulated rat model after oral dosing (in vivo, I...
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discovery of the oral Leukotriene C4 synthase inhibitor 1s 2s 2 5 5 chloro 2 4 difluorophenyl 2 fluoro 2 methylpropyl amino 3 methoxypyrazin 2 yl carbonyl cyclopropanecarboxylic acid azd9898 as a new treatment for asthma
Journal of Medicinal Chemistry, 2019Co-Authors: Magnus Munck Af Rosenschöld, Petra Johannesson, Antonios Nikitidis, Christian Tyrchan, Hui-fang Chang, Robert Ronn, Dave Chapman, Victoria Ullah, Grigorios Nikitidis, Pernilla GladerAbstract:While bronchodilators and inhaled corticosteroids are the mainstay of asthma treatment, up to 50% of asthmatics remain uncontrolled. Many studies show that the cysteinyl Leukotriene cascade remains highly activated in some asthmatics, even those on high-dose inhaled or oral corticosteroids. Hence, inhibition of the Leukotriene C4 synthase (LTC4S) enzyme could provide a new and differentiated core treatment for patients with a highly activated cysteinyl Leukotriene cascade. Starting from a screening hit (3), a program to discover oral inhibitors of LTC4S led to (1S,2S)-2-({5-[(5-chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid (AZD9898) (36), a picomolar LTC4S inhibitor (IC50 = 0.28 nM) with high lipophilic ligand efficiency (LLE = 8.5), which displays nanomolar potency in cells (peripheral blood mononuclear cell, IC50,free = 6.2 nM) and good in vivo pharmacodynamics in a calcium ionophore-stimulated rat model after oral dosing (in vivo, IC50,free = 34 nM). Compound 36 mitigates the GABA binding, hepatic toxicity signal, and in vivo toxicology findings of an early lead compound 7 with a human dose predicted to be 30 mg once daily.
Grigorios Nikitidis - One of the best experts on this subject based on the ideXlab platform.
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discovery of the oral Leukotriene C4 synthase inhibitor 1s 2s 2 5 5 chloro 2 4 difluorophenyl 2 fluoro 2 methylpropyl amino 3 methoxypyrazin 2 yl carbonyl cyclopropanecarboxylic acid azd9898 as a new treatment for asthma
Journal of Medicinal Chemistry, 2019Co-Authors: Magnus Munck Af Rosenschöld, Petra Johannesson, Antonios Nikitidis, Christian Tyrchan, Hui-fang Chang, Robert Ronn, Dave Chapman, Victoria Ullah, Grigorios Nikitidis, Pernilla GladerAbstract:While bronchodilators and inhaled corticosteroids are the mainstay of asthma treatment, up to 50% of asthmatics remain uncontrolled. Many studies show that the cysteinyl Leukotriene cascade remains highly activated in some asthmatics, even those on high-dose inhaled or oral corticosteroids. Hence, inhibition of the Leukotriene C4 synthase (LTC4S) enzyme could provide a new and differentiated core treatment for patients with a highly activated cysteinyl Leukotriene cascade. Starting from a screening hit (3), a program to discover oral inhibitors of LTC4S led to (1S,2S)-2-({5-[(5-chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid (AZD9898) (36), a picomolar LTC4S inhibitor (IC50 = 0.28 nM) with high lipophilic ligand efficiency (LLE = 8.5), which displays nanomolar potency in cells (peripheral blood mononuclear cell, IC50,free = 6.2 nM) and good in vivo pharmacodynamics in a calcium ionophore-stimulated rat model after oral dosing (in vivo, I...
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discovery of the oral Leukotriene C4 synthase inhibitor 1s 2s 2 5 5 chloro 2 4 difluorophenyl 2 fluoro 2 methylpropyl amino 3 methoxypyrazin 2 yl carbonyl cyclopropanecarboxylic acid azd9898 as a new treatment for asthma
Journal of Medicinal Chemistry, 2019Co-Authors: Magnus Munck Af Rosenschöld, Petra Johannesson, Antonios Nikitidis, Christian Tyrchan, Hui-fang Chang, Robert Ronn, Dave Chapman, Victoria Ullah, Grigorios Nikitidis, Pernilla GladerAbstract:While bronchodilators and inhaled corticosteroids are the mainstay of asthma treatment, up to 50% of asthmatics remain uncontrolled. Many studies show that the cysteinyl Leukotriene cascade remains highly activated in some asthmatics, even those on high-dose inhaled or oral corticosteroids. Hence, inhibition of the Leukotriene C4 synthase (LTC4S) enzyme could provide a new and differentiated core treatment for patients with a highly activated cysteinyl Leukotriene cascade. Starting from a screening hit (3), a program to discover oral inhibitors of LTC4S led to (1S,2S)-2-({5-[(5-chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid (AZD9898) (36), a picomolar LTC4S inhibitor (IC50 = 0.28 nM) with high lipophilic ligand efficiency (LLE = 8.5), which displays nanomolar potency in cells (peripheral blood mononuclear cell, IC50,free = 6.2 nM) and good in vivo pharmacodynamics in a calcium ionophore-stimulated rat model after oral dosing (in vivo, IC50,free = 34 nM). Compound 36 mitigates the GABA binding, hepatic toxicity signal, and in vivo toxicology findings of an early lead compound 7 with a human dose predicted to be 30 mg once daily.