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 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
High throughput screening identified a phenoxyacetic acid scaffold as a novel CRTh2 receptor antagonist chemotype, which could be optimised to furnish a compound with functional potency for inhibition of human eosinophil shape change and oral bioavailability in the rat.
Subject(s)
Acetates/pharmacology , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Acetates/chemistry , Animals , Biological Availability , Eosinophils/drug effects , Humans , Rats , 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.
Subject(s)
Adenosine A2 Receptor Antagonists , Adenosine A3 Receptor Antagonists , Receptor, Adenosine A2B/metabolism , Receptor, Adenosine A3/metabolism , Thiazoles , Animals , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/pharmacokinetics , Heterocyclic Compounds/pharmacology , Rats , Rats, Wistar , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/pharmacokinetics , Thiazoles/pharmacologyABSTRACT
A series of novel corticosteroid derivatives featuring C-17 furoate ester functionality have been synthesised. Profiling in vitro and in vivo has resulted in the identification of a compound with a longer duration of action and a lower oral side effect profile in rodents compared to budesonide.
