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
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.
Subject(s)
Androstenes/chemical synthesis , Esters/chemical synthesis , Glucocorticoids/chemical synthesis , Receptors, Glucocorticoid/agonists , Androstenes/pharmacokinetics , Androstenes/pharmacology , Animals , Biological Availability , Cell Line , Eosinophilia/drug therapy , Esters/pharmacokinetics , Esters/pharmacology , Glucocorticoids/pharmacokinetics , Glucocorticoids/pharmacology , Humans , Macrophages/cytology , Organ Size/drug effects , Protein Binding , Rats , Structure-Activity Relationship , Thymus Gland/drug effects , Tumor Necrosis Factor-alpha/analysis , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
The synthesis of a series of long-chain formoterol analogues in which the terminal ether residue of the beta-phenethyl-amino-substituent has been extended beyond the methyl ether residue present in the parent compound are described. Evaluation of these analogues as beta(2)-adrenoceptor agonists was used to provide an insight into the factors controlling the magnitude and duration of receptor activation.
Subject(s)
Adrenergic beta-2 Receptor Agonists , Adrenergic beta-Agonists/chemistry , Albuterol/analogs & derivatives , Ethanolamines/chemistry , Adrenergic beta-Agonists/chemical synthesis , Adrenergic beta-Agonists/pharmacology , Albuterol/chemistry , Animals , Ethanolamines/chemical synthesis , Ethanolamines/pharmacology , Formoterol Fumarate , Guinea Pigs , Humans , In Vitro Techniques , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Salmeterol Xinafoate , Stereoisomerism , Structure-Activity Relationship , Time FactorsABSTRACT
In clinical studies, several inhibitors of phosphodiesterase 5 (PDE5) have demonstrated utility in the treatment of erectile dysfunction. We describe herein a series of 8-aryl xanthine derivatives which function as potent PDE5 inhibitors with, in many cases, high levels of selectivity versus other PDE isoforms.
Subject(s)
Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/drug effects , Xanthines/pharmacology , Models, Molecular , Molecular Structure , Phosphodiesterase Inhibitors/chemistry , Xanthines/chemistryABSTRACT
PDE5 inhibitors based upon the xanthine scaffold 8 have been expediently synthesized using a solid-phase route. Attachment of the xanthine scaffold 8 using the Rink chloride linker 4 and N-1 functionalization using Mitsunobu chemistry is described. A library of compounds was produced in multi-milligram quantities with excellent purities and acceptable yields. The compounds were tested for their PDE5 inhibitory activity.
