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 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.
Subject(s)
Anti-Asthmatic Agents/pharmacology , Asthma/drug therapy , Drug Discovery , Enzyme Inhibitors/pharmacology , Glutathione Transferase/antagonists & inhibitors , Pyrazines/pharmacology , 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 RelationshipABSTRACT
The mechanism-based risk for hyperkalemia has limited the use of mineralocorticoid receptor antagonists (MRAs) like eplerenone in cardio-renal diseases. Here, we describe the structure and property-driven lead generation and optimization, which resulted in identification of MR modulators ( S)-1 and ( S)-33. Both compounds were partial MRAs but still demonstrated equally efficacious organ protection as eplerenone after 4 weeks of treatment in uni-nephrectomized rats on high-salt diet and aldosterone infusion. Importantly, and in sharp contrast to eplerenone, this was achieved without substantial changes to the urine Na+/K+ ratio after acute treatment in rat, which predicts a reduced risk for hyperkalemia. This work led to selection of ( S)-1 (AZD9977) as the clinical candidate for treating MR-mediated cardio-renal diseases, including chronic kidney disease and heart failure. On the basis of our findings, we propose an empirical model for prediction of compounds with low risk of affecting the urinary Na+/K+ ratio in vivo.
Subject(s)
Homeostasis/drug effects , Mineralocorticoid Receptor Antagonists/pharmacology , Oxazines/pharmacology , Potassium/metabolism , Protective Agents/pharmacology , Sodium/metabolism , Animals , Heart/drug effects , Humans , Kidney/drug effects , Male , Mineralocorticoid Receptor Antagonists/chemical synthesis , Mineralocorticoid Receptor Antagonists/metabolism , Molecular Structure , Oxazines/chemical synthesis , Oxazines/metabolism , Potassium/urine , Protective Agents/chemical synthesis , Protective Agents/metabolism , Rats, Sprague-Dawley , Rats, Wistar , Receptors, Mineralocorticoid/metabolism , Renal Insufficiency, Chronic/drug therapy , Sodium/urine , Structure-Activity RelationshipABSTRACT
A class of potent, nonsteroidal, selective indazole ether-based glucocorticoid receptor modulators (SGRMs) was developed for the inhaled treatment of respiratory diseases. Starting from an orally available compound with demonstrated anti-inflammatory activity in rat, a soft-drug strategy was implemented to ensure rapid elimination of drug candidates to minimize systemic GR activation. The first clinical candidate 1b (AZD5423) displayed a potent inhibition of lung edema in a rat model of allergic airway inflammation following dry powder inhalation combined with a moderate systemic GR-effect, assessed as thymic involution. Further optimization of inhaled drug properties provided a second, equally potent, candidate, 15m (AZD7594), that demonstrated an improved therapeutic ratio over the benchmark inhaled corticosteroid 3 (fluticasone propionate) and prolonged the inhibition of lung edema, indicating potential for once-daily treatment.
Subject(s)
Acetamides/therapeutic use , Indazoles/therapeutic use , Pulmonary Edema/drug therapy , Receptors, Glucocorticoid/drug effects , Administration, Inhalation , Aged , Animals , Dose-Response Relationship, Drug , Humans , Mass Spectrometry , Powders , Proton Magnetic Resonance Spectroscopy , RatsABSTRACT
The T-type calcium channel inhibitor Mibefradil was reported to protect the heart from atrial remodeling, a key process involved in the development of atrial fibrillation and arrhythmias. Mibefradil is not a selective T-type calcium channel inhibitor and also affects the function of different ion channels. Our aim was to develop a selective T-type calcium channel inhibitor to validate the importance of T-type-related pharmacology in atrial fibrillation. Structural optimisation of a previously disclosed hit series focussed on minimising exposure to the central nervous system and improving pharmacokinetic properties, while maintain adequate potency and selectivity. This resulted in the design of N-[[1-[2-(tert-butylcarbamoylamino)ethyl]-4-(hydroxymethyl)-4-piperidyl]methyl]-3,5-dichloro-benzamide, a novel, selective, peripherally restricted chemical probe to verify the role of T-type calcium channel inhibition on atrial fibrillation protection.
