ABSTRACT
A 1,2,4-triazole motif was employed as a bioisostere for the ester commonly used in muscarinic antagonists, and subsequent integrative conjugation to a ß2 agonist quinolinone furnished a new class of bifunctional MABAs for the treatment of COPD. Medicinal chemistry optimization using the principles of 'inhalation by design' furnished a clinical candidate with desirable pharmacological, pharmacokinetic and biopharmaceutical properties.
Subject(s)
Adrenergic beta-2 Receptor Agonists/chemical synthesis , Bronchodilator Agents/chemical synthesis , Muscarinic Antagonists/chemical synthesis , Pulmonary Disease, Chronic Obstructive/drug therapy , Triazoles/chemical synthesis , Adrenergic beta-2 Receptor Agonists/pharmacokinetics , Adrenergic beta-2 Receptor Agonists/pharmacology , Animals , Biological Availability , Bronchoconstriction/drug effects , Bronchodilator Agents/pharmacokinetics , Bronchodilator Agents/pharmacology , CHO Cells , Cricetulus , Dogs , Humans , Ipratropium/pharmacology , Muscarinic Antagonists/pharmacokinetics , Muscarinic Antagonists/pharmacology , Rats , Receptor, Muscarinic M3/antagonists & inhibitors , Salmeterol Xinafoate/pharmacology , Tiotropium Bromide/pharmacology , Triazoles/pharmacokinetics , Triazoles/pharmacologyABSTRACT
This paper describes the identification and optimization of a novel series of DFG-out binding p38 inhibitors as inhaled agents for the treatment of chronic obstructive pulmonary disease. Structure based drug design and "inhalation by design" principles have been applied to the optimization of the lead series exemplied by compound 1a. Analogues have been designed to be potent and selective for p38, with an emphasis on slow enzyme dissociation kinetics to deliver prolonged lung p38 inhibition. Pharmacokinetic properties were tuned with high intrinsic clearance and low oral bioavailability in mind, to minimize systemic exposure and reduce systemically driven adverse events. High CYP mediated clearance and glucuronidation were targeted to achieve high intrinsic clearance coupled with multiple routes of clearance to minimize drug-drug interactions. Furthermore, pharmaceutical properties such as stability, crystallinity, and solubility were considered to ensure compatibility with a dry powder inhaler. 1ab (PF-03715455) was subsequently identified as a clinical candidate from this series with efficacy and safety profiles confirming its potential as an inhaled agent for the treatment of COPD.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Azabicyclo Compounds/chemical synthesis , Methylurea Compounds/chemical synthesis , Pulmonary Disease, Chronic Obstructive/drug therapy , Pyrazoles/chemical synthesis , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Administration, Inhalation , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Azabicyclo Compounds/pharmacokinetics , Azabicyclo Compounds/pharmacology , Binding Sites , Cell Membrane Permeability , Crystallography, X-Ray , Dogs , Drug Stability , Humans , In Vitro Techniques , Kinetics , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Methylurea Compounds/pharmacokinetics , Methylurea Compounds/pharmacology , Models, Molecular , Protein Binding , Protein Conformation , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Rats , Solubility , Surface Plasmon Resonance , Tumor Necrosis Factor-alpha/biosynthesis , p38 Mitogen-Activated Protein Kinases/chemistryABSTRACT
A novel tertiary amine series of potent muscarinic M(3) receptor antagonists are described that exhibit potential as inhaled long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease. Geminal dimethyl functionality present in this series of compounds confers very long dissociative half-life (slow off-rate) from the M(3) receptor that mediates very long-lasting smooth muscle relaxation in guinea pig tracheal strips. Optimization of pharmacokinetic properties was achieved by combining rapid oxidative clearance with targeted introduction of a phenolic moiety to secure rapid glucuronidation. Together, these attributes minimize systemic exposure following inhalation, mitigate potential drug-drug interactions, and reduce systemically mediated adverse events. Compound 47 (PF-3635659) is identified as a Phase II clinical candidate from this series with in vivo duration of action studies confirming its potential for once-daily use in humans.
Subject(s)
Azetidines/chemical synthesis , Bronchodilator Agents/chemical synthesis , Diphenylacetic Acids/chemical synthesis , Pulmonary Disease, Chronic Obstructive/drug therapy , Receptor, Muscarinic M3/antagonists & inhibitors , Administration, Inhalation , Animals , Azetidines/chemistry , Azetidines/pharmacology , Bronchodilator Agents/chemistry , Bronchodilator Agents/pharmacology , CHO Cells , Cell Line , Cell Membrane Permeability , Cricetinae , Cricetulus , Diphenylacetic Acids/chemistry , Diphenylacetic Acids/pharmacology , Dogs , Female , Guinea Pigs , Hepatocytes/metabolism , Humans , In Vitro Techniques , Kinetics , Male , Microsomes, Liver/metabolism , Muscle Relaxation/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Radioligand Assay , Rats , Receptor, Muscarinic M3/metabolism , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/metabolism , Stereoisomerism , Structure-Activity Relationship , Trachea/drug effects , Trachea/physiologyABSTRACT
This paper describes the successful design and development of dual pharmacology ß-2 agonists-M3 antagonists, for the treatment of chronic obstructive pulmonary disorder using the principles of 'inhalation by design'. A key feature of this work is the combination of balanced potency and pharmacodynamic duration with desirable pharmacokinetic and material properties, whilst keeping synthetic complexity to a minimum.
Subject(s)
Adrenergic beta-2 Receptor Agonists , Drug Design , Muscarinic Antagonists , Pulmonary Disease, Chronic Obstructive/drug therapy , Administration, Inhalation , Adrenergic beta-2 Receptor Agonists/administration & dosage , Animals , Benzhydryl Compounds/administration & dosage , Cresols/administration & dosage , Drug Therapy, Combination , Guinea Pigs , Molecular Structure , Muscarinic Antagonists/administration & dosage , Phenylpropanolamine/administration & dosage , Tolterodine TartrateABSTRACT
A novel series of potent and selective sulfonamide derived ß(2)-adrenoreceptor agonists are described that exhibit potential as inhaled ultra-long-acting bronchodilators for the treatment of asthma and chronic obstructive pulmonary disease. Analogues from this series mediate very long-lasting smooth muscle relaxation in guinea pig tracheal strips. The sulfonamide agonist headgroup confers high levels of intrinsic crystallinity that could relate to the acidic sulfonamide motif supporting a zwitterionic form in the solid state. Optimization of pharmacokinetic properties was achieved through targeted introduction of a phenolic moiety to support rapid phase II clearance, thereby minimizing systemic exposure following inhalation and reducing systemically mediated adverse events. Compound 38 (PF-610355) is identified as a clinical candidate from this series, with in vivo duration of action studies confirming its potential for once-daily use in humans. Compound 38 is currently in advanced phase II clinical studies.
Subject(s)
Adrenergic beta-2 Receptor Agonists , Adrenergic beta-Agonists/chemical synthesis , Asthma/drug therapy , Benzeneacetamides/chemical synthesis , Pulmonary Disease, Chronic Obstructive/drug therapy , Sulfonamides/chemical synthesis , Administration, Inhalation , Adrenergic beta-Agonists/pharmacokinetics , Adrenergic beta-Agonists/pharmacology , Animals , Benzeneacetamides/pharmacokinetics , Benzeneacetamides/pharmacology , Bronchoconstriction/drug effects , CHO Cells , Cricetinae , Cricetulus , Crystallography, X-Ray , Dogs , Female , Guinea Pigs , Hepatocytes/metabolism , Humans , In Vitro Techniques , Liver/metabolism , Male , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Models, Molecular , Molecular Structure , Muscle, Smooth/drug effects , Muscle, Smooth/physiopathology , Rats , Stereoisomerism , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacology , Trachea/drug effects , Trachea/metabolism , Trachea/physiopathologyABSTRACT
The sustained delivery of multiple agents to the lung offers potential benefits to patients. This study explores the preparation of highly respirable dual-loaded spray-dried double emulsions. Spray-dried powders were produced from water-in-oil-in-water (w/o/w) double emulsions, containing salbutamol sulphate and/or beclometasone dipropionate in varying phases. The double emulsions contained the drug release modifier polylactide co-glycolide (PLGA 50 : 50) in the intermediate organic phase of the original micro-emulsion and low molecular weight chitosan (Mw<190 kDa: emulsion stabilizer) and leucine (aerosolization enhancer) in the tertiary aqueous phase. Following spray-drying resultant powders were physically characterized: with in vitro aerosolization performance and drug release investigated using a Multi-Stage Liquid Impinger and modified USP II dissolution apparatus, respectively. Powders generated were of a respirable size exhibiting emitted doses of over 95% and fine particle fractions of up to 60% of the total loaded dose. Sustained drug release profiles were observed during dissolution for powders containing agents in the primary aqueous and secondary organic phases of the original micro-emulsion; the burst release of agents was witnessed from the tertiary aqueous phase. The novel spray-dried emulsions from this study would be expected to deposit and display sustained release character in the lung.
Subject(s)
Adrenergic beta-Agonists/administration & dosage , Albuterol/administration & dosage , Anti-Asthmatic Agents/administration & dosage , Beclomethasone/administration & dosage , Delayed-Action Preparations/chemistry , Emulsions/chemistry , Chitosan/chemistry , Lactic Acid/chemistry , Particle Size , Polyglycolic Acid/chemistry , Polylactic Acid-Polyglycolic Acid Copolymer , SolubilityABSTRACT
The controlled co-delivery of multiple agents to the lung offers potential benefits to patients. This study investigated the preparation and characterisation of highly respirable spray-dried powders displaying the sustained release of two chemically distinct therapeutic agents. Spray-dried powders were produced from 30% (v/v) aqueous ethanol formulations that contained hydrophilic (terbutaline sulphate) and hydrophobic (beclometasone dipropionate) model drugs, chitosan (as a drug release modifier) and leucine (aerosolisation enhancer). The influence of chitosan molecular weight on spray-drying thermal efficiency, aerosol performance and drug release profile was investigated. Resultant powders were physically characterised: with in vitro aerosolisation performance and drug release profile investigated by the Multi-Stage Liquid Impinger and modified USP II dissolution apparatus, respectively. It was found that increased chitosan molecular weight gave increased spray-drying thermal efficiency. The powders generated were of a suitable size for inhalation-with emitted doses over 90% and fine particle fractions up to 72% of the loaded dose. Sustained drug release profiles were observed in dissolution tests for both agents: increased chitosan molecular weight associated with increased duration of drug release. The controlled co-delivery of hydrophilic and hydrophobic entities underlines the capability of spray drying to produce respirable particles with sustained release for delivery to the lung.
Subject(s)
Chitosan/administration & dosage , Drug Delivery Systems/methods , Leucine/administration & dosage , Administration, Inhalation , Chemistry, Pharmaceutical/methods , Chitosan/metabolism , Leucine/metabolism , Lung/drug effects , Lung/metabolism , Particle Size , PowdersABSTRACT
In this study, we describe the preparation of highly dispersible dry powders for pulmonary drug delivery that display sustained drug release characteristics. Powders were prepared by spray-drying 30% v/v aqueous ethanol formulations containing terbutaline sulfate as a model drug, chitosan as a drug release modifier and leucine as an aerosolisation enhancer. The influence of chitosan molecular weight on the drug release profile was investigated by using low, medium and high molecular weight chitosan or combinations thereof. Following spray-drying, resultant powders were characterised using scanning electron microscopy, laser diffraction, tapped density analysis, differential scanning calorimetry and thermogravitational analysis. The in vitro aerosolisation performance and drug release profile were investigated using Multi-Stage Liquid Impinger analysis and modified USP II dissolution apparatus, respectively. The powders generated were of a suitable aerodynamic size for inhalation, had low moisture content and were amorphous in nature. The powders were highly dispersible, with emitted doses of over 90% and fine particle fractions of up to 82% of the total loaded dose, and mass median aerodynamic diameters of less than 2.5microm. A sustained drug release profile was observed during dissolution testing; increasing the molecular weight of the chitosan in the formulation increased the duration of drug release.
