ABSTRACT
Starting from our previously described PI3Kγ inhibitors, we describe the exploration of structure-activity relationships that led to the discovery of highly potent dual PI3Kγδ inhibitors. We explored changes in two positions of the molecules, including macrocyclization, but ultimately identified a simpler series with the desired potency profile that had suitable physicochemical properties for inhalation. We were able to demonstrate efficacy in a rat ovalbumin challenge model of allergic asthma and in cells derived from asthmatic patients. The optimized compound, AZD8154, has a long duration of action in the lung and low systemic exposure coupled with high selectivity against off-targets.
Subject(s)
Asthma/drug therapy , Class Ib Phosphatidylinositol 3-Kinase/metabolism , Protein Kinase Inhibitors/therapeutic use , Sulfonamides/therapeutic use , Thiazoles/therapeutic use , Animals , Asthma/chemically induced , Class I Phosphatidylinositol 3-Kinases/metabolism , Crystallography, X-Ray , Humans , Leukocytes, Mononuclear/drug effects , Male , Molecular Structure , Ovalbumin , Phosphatidylinositol 3-Kinases/metabolism , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacokinetics , Rats, Inbred BN , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/metabolism , Sulfonamides/pharmacokinetics , Thiazoles/chemical synthesis , Thiazoles/metabolism , Thiazoles/pharmacokineticsABSTRACT
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
Synthetic glucocorticoids (GC) are essential for the treatment of a broad range of inflammatory diseases. However, their use is limited by target related adverse effects on, e.g., glucose homeostasis and bone metabolism. Starting from a nonsteroidal GR ligand (4) that is a full agonist in reporter gene assays, we exploited key functional triggers within the receptor, generating a range of structurally diverse partial agonists. Of these, only a narrow subset exhibited full anti-inflammatory efficacy and a significantly reduced impact on adverse effect markers in human cell assays compared to prednisolone. This led to the discovery of AZD9567 (15) with excellent in vivo efficacy when dosed orally in a rat model of joint inflammation. Compound 15 is currently being evaluated in clinical trials comparing the efficacy and side effect markers with those of prednisolone.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Drug Discovery , Indazoles/pharmacology , Pyridines/pharmacology , Receptors, Glucocorticoid/agonists , Administration, Oral , Animals , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/adverse effects , Cell Line , Humans , Indazoles/administration & dosage , Indazoles/adverse effects , Ligands , Pyridines/administration & dosage , Pyridines/adverse effects , 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.
Subject(s)
Benzamides/chemistry , Calcium Channel Blockers/chemistry , Calcium Channels, T-Type/chemistry , Animals , Benzamides/chemical synthesis , Benzamides/pharmacokinetics , Calcium Channel Blockers/chemical synthesis , Calcium Channel Blockers/pharmacokinetics , Calcium Channels, T-Type/metabolism , Dogs , Drug Evaluation, Preclinical , Half-Life , Heart Rate/drug effects , Humans , Structure-Activity RelationshipABSTRACT
Chemical evolution of a HTS-based fragment hit resulted in the identification of N-(1-adamantyl)-2-[4-(2-tetrahydropyran-4-ylethyl)piperazin-1-yl]acetamide, a novel, selective T-type calcium channel (Ca(v)3.2) inhibitor with in vivo antihypertensive effect in rats.
