ABSTRACT
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
Heteroarylalanine derivatives 4 were designed as potential inhibitors of neutral endopeptidase (NEP EC 3.4.24.11). Selectivity over other zinc metalloproteinases was explored through occupation of the S2' subsite within NEP. Structural optimisation led to the identification of 5-phenyl oxazole 4f, a potent and selective NEP inhibitor. A crystal structure of the inhibitor bound complex is reported.
