ABSTRACT
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel are established as the primary causative factor in the devastating lung disease cystic fibrosis (CF). More recently, cigarette smoke exposure has been shown to be associated with dysfunctional airway epithelial ion transport, suggesting a role for CFTR in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, the identification and characterization of a high throughput screening hit 6 as a potentiator of mutant human F508del and wild-type CFTR channels is reported. The design, synthesis, and biological evaluation of compounds 7-33 to establish structure-activity relationships of the scaffold are described, leading to the identification of clinical development compound icenticaftor (QBW251) 33, which has subsequently progressed to deliver two positive clinical proofs of concept in patients with CF and COPD and is now being further developed as a novel therapeutic approach for COPD patients.
Subject(s)
Aminopyridines/chemistry , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Administration, Oral , Aminopyridines/metabolism , Aminopyridines/therapeutic use , Animals , Cystic Fibrosis/drug therapy , Cystic Fibrosis Transmembrane Conductance Regulator/antagonists & inhibitors , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Disease Models, Animal , Drug Evaluation, Preclinical , Gene Deletion , Half-Life , Humans , Protein Binding , Pulmonary Disease, Chronic Obstructive/drug therapy , Rats , Rats, Sprague-Dawley , Solubility , Structure-Activity RelationshipABSTRACT
[This corrects the article DOI: 10.1021/acsmedchemlett.7b00157.].
ABSTRACT
Further optimization of an initial DP2 receptor antagonist clinical candidate NVP-QAV680 led to the discovery of a follow-up molecule 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid (compound 11, NVP-QAW039, fevipiprant), which exhibits improved potency on human eosinophils and Th2 cells, together with a longer receptor residence time, and is currently in clinical trials for severe asthma.
ABSTRACT
Herein we describe the optimization of a series of PDE4 inhibitors, with special focus on solubility and pharamcokinetics, to clinical compound 2, 4-(8-(3-fluorophenyl)-1,7-naphthyridin-6-yl)transcyclohexanecarboxylic acid. Although compound 2 produces emesis in humans when given as a single dose, its exemplary pharmacokinetic properties enabled a novel dosing regime comprising multiple escalating doses and the resultant achievement of high plasma drug levels without associated nausea or emesis.
Subject(s)
Cyclohexanecarboxylic Acids/chemistry , Naphthyridines/chemistry , Phosphodiesterase 4 Inhibitors/chemistry , Pulmonary Disease, Chronic Obstructive/drug therapy , Animals , Cyclohexanecarboxylic Acids/pharmacokinetics , Cyclohexanecarboxylic Acids/pharmacology , Dose-Response Relationship, Drug , Humans , Naphthyridines/pharmacokinetics , Naphthyridines/pharmacology , Nausea/chemically induced , Phosphodiesterase 4 Inhibitors/pharmacokinetics , Phosphodiesterase 4 Inhibitors/pharmacology , Rats , Solubility , Structure-Activity Relationship , Thermodynamics , Vomiting/chemically inducedABSTRACT
The optimisation of two series of 4-hydroxybenzothiazolone derived ß2-adrenoceptor agonists, bearing α-substituted cyclopentyl and ß-phenethyl amino-substituents, as inhaled long-acting bronchodilators is described. Analogues were selected for synthesis using a lipophilicity based hypothesis to achieve the targeted rapid onset of action in combination with a long duration of action. The profiling of the two series led to identification of the α-substituted cyclopentyl analogue 2 as the optimal compound with a comparable profile to the inhaled once-daily long-acting ß2-adrenoceptor agonist indacaterol. On the basis of these data 2 was promoted as the backup development candidate to indacaterol from the Novartis LABA project.
Subject(s)
Adrenergic beta-2 Receptor Agonists/administration & dosage , Adrenergic beta-2 Receptor Agonists/pharmacology , Benzothiazoles/administration & dosage , Benzothiazoles/pharmacology , Receptors, Adrenergic, beta-2/metabolism , Administration, Inhalation , Adrenergic beta-2 Receptor Agonists/chemistry , Animals , Benzothiazoles/chemistry , Dose-Response Relationship, Drug , Guinea Pigs , Molecular StructureABSTRACT
Using a parallel synthesis approach to target a non-conserved region of the PI3K catalytic domain a pan-PI3K inhibitor 1 was elaborated to provide alpha, delta and gamma isoform selective Class I PI3K inhibitors 21, 24, 26 and 27. The compounds had good cellular activity and were selective against protein kinases and other members of the PI3K superfamily including mTOR and DNA-PK.
Subject(s)
Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Thiazoles/chemistry , Thiazoles/pharmacology , Animals , Catalytic Domain , Female , Humans , Mice , Models, Molecular , Phosphatidylinositol 3-Kinases/chemistry , Phosphatidylinositol 3-Kinases/metabolism , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/chemistry , Protein Isoforms/metabolism , Protein Kinase Inhibitors/pharmacokinetics , Rats , Signal Transduction/drug effects , Thiazoles/pharmacokineticsABSTRACT
The solubility-driven optimization of a series of 1,7-napthyridine phosphodiesterase-4 inhibitors is described. Directed structural changes resulted in increased aqueous solubility, enabling superior pharmacokinetic properties with retention of PDE4 inhibition. A range of potent and orally bioavailable compounds with good in vivo efficacy in animal models of inflammation and reduced emetic potential compared to previously described drugs were synthesized. Compound 2d was taken forward as a clinical candidate for the treatment of COPD.
Subject(s)
Phosphodiesterase 4 Inhibitors/chemistry , Phosphodiesterase 4 Inhibitors/pharmacology , Animals , Cells, Cultured , Disease Models, Animal , Drug Design , Drug Evaluation, Preclinical , Humans , Magnetic Resonance Spectroscopy , Mice , Models, Molecular , Phosphodiesterase 4 Inhibitors/pharmacokinetics , Phosphodiesterase 4 Inhibitors/therapeutic use , Rats , Solubility , Vomiting/drug therapyABSTRACT
Following a lipophilicity-based hypothesis, an 8-hydroxyquinolinone 2-aminoindan derived series of beta(2)-adrenoceptor agonists have been prepared and evaluated for their potential as inhaled ultralong-acting bronchodilators. Determination of their activities at the human beta(2)-adrenoceptor receptor showed symmetrical substitution of the 2-aminoindan moiety at the 5- and 6-positions delivered the targeted intermediate potency and intrinsic-efficacy profiles relative to a series of clinical reference beta(2)-adrenoceptor agonists. Further assessment with an in vitro superfused electrically stimulated guinea-pig tracheal-strip assay established the onset and duration of action time courses, which could be rationalized by considering the lipophilicity, potency, and intrinsic efficacy of the compounds. From these studies the 5,6-diethylindan analogue indacaterol 1c was shown to possess a unique profile of combining a rapid onset of action with a long duration of action. Further in vivo profiling of 1c supported the long duration of action and a wide therapeutic index following administration to the lung, which led to the compound being selected as a development candidate.
Subject(s)
Adrenergic beta-2 Receptor Agonists , Bronchodilator Agents/chemistry , Indans/pharmacology , Quinolones/pharmacology , Administration, Inhalation , Animals , Guinea Pigs , Humans , Hydrophobic and Hydrophilic Interactions , Indans/administration & dosage , Indans/pharmacokinetics , Quinolones/administration & dosage , Quinolones/pharmacokinetics , Structure-Activity RelationshipABSTRACT
Inhibitors of PDE5 are useful therapeutic agents for treatment of erectile dysfunction. A series of novel xanthine derivatives has been identified as potent inhibitors of PDE5, with good levels of selectivity against other PDE isoforms, including PDE6. Studies in the dog indicate excellent oral bioavailability for compound 21.
Subject(s)
3',5'-Cyclic-GMP Phosphodiesterases/antagonists & inhibitors , Xanthines/pharmacology , Animals , Biological Availability , Cattle , Cyclic Nucleotide Phosphodiesterases, Type 5 , Dogs , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Erectile Dysfunction/drug therapy , Humans , Inhibitory Concentration 50 , Male , Pharmacokinetics , Protein Isoforms/drug effects , Structure-Activity Relationship , Xanthines/chemistryABSTRACT
The synthesis and SAR of 5-heterocycle-substituted aminothiazole adenosine receptor antagonists is described. Several compounds show high affinity and selectivity for the A2B and A3 receptors. One compound (5f) shows good ADME properties in the rat and as such may be an important new compound in testing the current hypotheses proposing a therapeutic role for a dual A2B/A3 antagonist in allergic diseases.