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
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
COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. The pharmacological and pharmacokinetic SAR of a series of inhaled A(2A) agonists is described leading through to human pharmacokinetic data for a clinical candidate.
Subject(s)
Adenosine A2 Receptor Agonists , Pulmonary Disease, Chronic Obstructive/drug therapy , Adenosine/analogs & derivatives , Adenosine/chemistry , Administration, Inhalation , Adolescent , Adult , Animals , Chemistry, Pharmaceutical/methods , Drug Design , Humans , Inhibitory Concentration 50 , Lung/drug effects , Male , Middle Aged , Models, Chemical , Phenethylamines/chemistry , Purines/chemistry , Rats , Structure-Activity Relationship , Triazoles/chemistryABSTRACT
COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. A strategy of minimizing side-effect liability by maximizing systemic clearance was followed and pharmacological and pharmacokinetic SAR of a series of inhaled A(2A) agonists described. A sevenfold improvement in potency and 150-fold reduction in side-effect liability over the lead compound CGS-21680, were obtained.
