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2. 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

Author

Munck af Rosenschöld, Magnus, primary, Johannesson, Petra, additional, Nikitidis, Antonios, additional, Tyrchan, Christian, additional, Chang, Hui-Fang, additional, Rönn, Robert, additional, Chapman, Dave, additional, Ullah, Victoria, additional, Nikitidis, Grigorios, additional, Glader, Pernilla, additional, Käck, Helena, additional, Bonn, Britta, additional, Wågberg, Fredrik, additional, Björkstrand, Eva, additional, Andersson, Ulf, additional, Swedin, Linda, additional, Rohman, Mattias, additional, Andreasson, Theresa, additional, Bergström, Eva Lamm, additional, Jiang, Fanyi, additional, Zhou, Xiao-Hong, additional, Lundqvist, Anders J., additional, Malmberg, Anna, additional, Ek, Margareta, additional, Gordon, Euan, additional, Pettersen, Anna, additional, Ripa, Lena, additional, and Davis, Andrew M., additional

Published
2019
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3. 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

Author

Munck af Rosenschöld, Magnus, Johannesson, Petra, Nikitidis, Antonios, Tyrchan, Christian, Chang, Hui-Fang, Rönn, Robert, Chapman, Dave, Ullah, Victoria, Nikitidis, Grigorios, Glader, Pernilla, Käck, Helena, Bonn, Britta, Wågberg, Fredrik, Björkstrand, Eva, Andersson, Ulf, Swedin, Linda, Rohman, Mattias, Andreasson, Theresa, Bergström, Eva Lamm, Jiang, Fanyi, Zhou, Xiao-Hong, Lundqvist, Anders J., Malmberg, Anna, Ek, Margareta, Gordon, Euan, Pettersen, Anna, Ripa, Lena, and Davis, Andrew M.

Abstract

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 36mitigates the GABA binding, hepatic toxicity signal, and in vivo toxicology findings of an early lead compound 7with a human dose predicted to be 30 mg once daily.

Published
2024
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6. Role of oxytocin in glucose homeostasis and weight gain

Author

Björkstrand, Eva and Björkstrand, Eva

Abstract

The overall aim of this thesis was to study metabolic functions of oxytocin in particular in relation to glucose, insulin and glucagon. Application of oxytocin locally in the pancreas (microdialysis technique) increased insulin (RIA) and glucagon (RIA) release. Furthermore, specific binding-sites for oxytocin were demonstrated on the glucagon producing cc-cells (autoradiography). Oxytocin administered intracerebroventricularly (i.c.v., 2ng) increased plasma levels of insulin but not of glucagon. The effect on insulin was blocked by atropine. These data show that oxytocin may increase glucagon and insulin secretion by a local mechanism possibly linked to activation of cholinergic neurons in the dorsal motor nucleus of the vagal nerv (DMX). In support of a physiological role for oxytocin in glucose homeostasis, the increase of glucagon and glucose caused by suckling in lactating rats was blocked by a specific oxytocin receptor antagonist l-deamino-2-D-Tyr-(OEt)-4-Thr-8-Orn-oxytocin (Img/kg, s.c. Ferring, Malmö, Sweden). In addition, blood glucose levels were decreased in nonlactating female rats after injections (i.p) of the antagonist . Furthermore, 24 h of starvation in lactating rats, as well as insulin-induced hypoglycemia in male and in nonlactating female rats caused an increase in plasma levels of oxytocin. I.c.v. administration of oxytocin (2 ng) lowered CCK (RIA) and somatostatin (RIA) levels, an effect that was blocked by atropine pretreatment, indicating that vagal cholinergic fibers are involved. Oxytocin administered i.c.v. (5 µg) increased daily weight gain and food intake in female rats from a Sprague Dawley substrain, characterized by low spontaneus weight gain. The weight gain may not only be due to the increased food intake but also to an increased anabolic metabolism e.g. induced by the changed pattern of pancreatic and gastrointestinal hormones. The 5-HT1A receptor agonist 8-OH-DPAT (0.5 mg/kg s.c.) increased insulin and decreased CCK and somatosta

Published
1995

15. Discovery of the Oral Leukotriene C4 Synthase Inhibitor (1 S ,2 S )-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.

Author

Munck Af Rosenschöld M, Johannesson P, Nikitidis A, Tyrchan C, Chang HF, Rönn R, Chapman D, Ullah V, Nikitidis G, Glader P, Käck H, Bonn B, Wågberg F, Björkstrand E, Andersson U, Swedin L, Rohman M, Andreasson T, Bergström EL, Jiang F, Zhou XH, Lundqvist AJ, Malmberg A, Ek M, Gordon E, Pettersen A, Ripa L, and Davis AM

Subjects
Administration, Oral, Animals, Anti-Asthmatic Agents administration & dosage, Anti-Asthmatic Agents chemistry, Asthma metabolism, Disease Models, Animal, Dose-Response Relationship, Drug, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors chemistry, Glutathione Transferase metabolism, Humans, Molecular Structure, Pyrazines chemical synthesis, Pyrazines chemistry, Rats, Structure-Activity Relationship, Anti-Asthmatic Agents pharmacology, Asthma drug therapy, Drug Discovery, Enzyme Inhibitors pharmacology, Glutathione Transferase antagonists & inhibitors, Pyrazines pharmacology
Abstract

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 (1 S ,2 S )-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 (IC 50 = 0.28 nM) with high lipophilic ligand efficiency (LLE = 8.5), which displays nanomolar potency in cells (peripheral blood mononuclear cell, IC 50,free = 6.2 nM) and good in vivo pharmacodynamics in a calcium ionophore-stimulated rat model after oral dosing (in vivo, IC 50,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.

Published
2019
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16. Selective inhibition of 11 beta-hydroxysteroid dehydrogenase type 1 improves hepatic insulin sensitivity in hyperglycemic mice strains.

Author

Alberts P, Nilsson C, Selen G, Engblom LO, Edling NH, Norling S, Klingström G, Larsson C, Forsgren M, Ashkzari M, Nilsson CE, Fiedler M, Bergqvist E, Ohman B, Björkstrand E, and Abrahmsen LB

Subjects
11-beta-Hydroxysteroid Dehydrogenase Type 1 genetics, Adipose Tissue metabolism, Animals, Blood Glucose analysis, Diabetes Mellitus genetics, Diabetes Mellitus, Type 2 metabolism, Disease Models, Animal, Glucose Clamp Technique, Glucose Tolerance Test, Hyperglycemia genetics, Hyperinsulinism genetics, Hyperinsulinism metabolism, Insulin blood, Liver metabolism, Male, Mice, Mice, Inbred C57BL genetics, Obesity genetics, RNA, Messenger metabolism, 11-beta-Hydroxysteroid Dehydrogenase Type 1 antagonists & inhibitors, Enzyme Inhibitors pharmacology, Hyperglycemia metabolism, Insulin metabolism, Liver physiopathology, Piperazines pharmacology, Sulfonamides pharmacology, Thiazoles pharmacology
Abstract

11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) has been proposed as a new target for type 2 diabetes drugs. The aim of the present study was to assess the effects of inhibition of 11 beta-HSD1 on blood glucose levels, glucose tolerance, and insulin sensitivity in mouse models of type 2 diabetes. BVT.2733 is an isoform-selective inhibitor of mouse 11 beta-HSD1. Hyperglycemic and hyperinsulinemic ob/ob, db/db, KKAy, and normal C57BL/6J mice were orally administered BVT.2733 (200 mg/kg.d, twice daily). In hyperglycemic, but not in normal mice, BVT.2733 lowered circulating glucose (to 50-88% of control) and insulin (52-65%) levels. In oral glucose tolerance tests in ob/ob and KKAy mice, glucose concentrations were 65-75% of vehicle values after BVT.2733 treatment, and in KKAy mice insulin concentrations were decreased (62-74%). Euglycemic, hyperinsulinemic clamps demonstrated decreased endogenous glucose production (21-61%). Analysis of hepatic mRNA in KKAy mice showed reduced phosphoenolpyruvate carboxykinase mRNA (71%). A slight reduction in food intake was observed in ob/ob and KKAy mice. Cholesterol, triglycerides, and free fatty acid levels were decreased to 81-86% in KKAy mice after a 4-h fast. The results support previous suggestions that selective 11 beta-HSD1 inhibitors lower blood glucose levels and improve insulin sensitivity in different mouse models of type 2 diabetes.

Published
2003
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