ABSTRACT
Activation of muscarinic subtype 3 (M3) muscarinic cholinergic receptors (mAChRs) increases airway tone, whereas its blockade improves lung function and quality of life in patients with pulmonary diseases. The present study evaluated the pharmacological properties of a novel mAChR antagonist, GSK573719 (4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane; umeclidinium). The affinity (Ki) of GSK573719 for the cloned human M1-M5 mAChRs ranged from 0.05 to 0.16 nM. Dissociation of [(3)H]GSK573719 from the M3 mAChR was slower than that for the M2 mAChR [half-life (t1/2) values: 82 and 9 minutes, respectively]. In Chinese hamster ovary cells transfected with recombinant human M3 mAChRs, GSK573719 demonstrated picomolar potency (-log pA2 = 23.9 pM) in an acetylcholine (Ach)-mediated Ca(2+) mobilization assay. Concentration-response curves indicate competitive antagonism with partial reversibility after drug washout. Using isolated human bronchial strips, GSK573719 was also potent and showed competitive antagonism (-log pA2 = 316 pM) versus carbachol, and was slowly reversible in a concentration-dependent manner (1-100 nM). The time to 50% restoration of contraction at 10 nM was about 381 minutes (versus 413 minutes for tiotropium bromide). In mice, the ED50 value was 0.02 µg/mouse intranasally. In conscious guinea pigs, intratracheal administration of GSK573719 dose dependently blocked Ach-induced bronchoconstriction with long duration of action, and was comparable to tiotropium; 2.5 µg elicited 50% bronchoprotection for >24 hours. Thus, GSK573719 is a potent anticholinergic agent that demonstrates slow functional reversibility at the human M3 mAChR and long duration of action in animal models. This pharmacological profile translated into a 24-hour duration of bronchodilation in vivo, which suggested umeclidinium will be a once-daily inhaled treatment of pulmonary diseases.
Subject(s)
Lung Diseases/drug therapy , Muscarinic Antagonists/therapeutic use , Quinuclidines/therapeutic use , Administration, Inhalation , Animals , CHO Cells , Calcium/metabolism , Carbachol/pharmacology , Cholinergic Antagonists/pharmacology , Cricetinae , Cricetulus , Guinea Pigs , Kinetics , Lung/drug effects , Mice , Mice, Inbred BALB C , Muscarinic Agonists/pharmacology , Muscarinic Antagonists/administration & dosage , Plethysmography , Quinuclidines/administration & dosage , Receptor, Muscarinic M3/drug effects , Receptors, Muscarinic , Scopolamine Derivatives/pharmacology , Tiotropium BromideABSTRACT
Tyrosine ureas had been identified as potent muscarinic receptor antagonists with promising in vivo activity. Controlling the stereochemistry of the chiral quaternary ammonium center had proved to be a serious issue for this series, however. Herein we describe the preparation and SAR of tyrosine urea antagonists containing achiral quaternary ammonium centers. The most successful such moiety was the 2-methylimidazo[2,1-b][1,3]thiazol-7-ium group which yielded highly potent antagonists with long duration of action in an inhaled animal model of bronchoconstriction.
Subject(s)
Muscarinic Antagonists/chemistry , Quaternary Ammonium Compounds/chemistry , Receptors, Muscarinic/chemistry , Tyrosine/chemistry , Urea/analogs & derivatives , Animals , Bronchi/drug effects , Mice , Muscarinic Antagonists/chemical synthesis , Muscarinic Antagonists/pharmacology , Receptors, Muscarinic/metabolism , Structure-Activity Relationship , Urea/chemical synthesis , Urea/pharmacologyABSTRACT
A novel series of N-substituted tropane derivatives was characterized as potent muscarinic acetylcholine receptor antagonists (mAChRs). Kinetic washout studies showed that the N-endosubstituted analog 24 displayed much slower reversibility at mAChRs than the methyl-substituted parent molecule darotropium. In addition, it was shown that this characteristic appeared to translate into enhanced which duration of action in a mouse model of bronchonstriction.
Subject(s)
Muscarinic Antagonists/chemical synthesis , Tropanes/chemical synthesis , Animals , Bronchial Diseases/drug therapy , Drug Design , Mice , Muscarinic Antagonists/pharmacology , Receptors, Muscarinic/drug effects , Structure-Activity Relationship , Tropanes/pharmacologyABSTRACT
Novel tropane derivatives were characterized as muscarinic acetylcholine receptor antagonists (mAChRs). Through optimization of the structure-activity relationship around the tropane scaffold, the quaternary ammonium salt 34 was identified as a very potent M(3) mAChR antagonist. The compound was functionally active and displayed greater than 24 h duration of action in a mouse model of bronchoconstriction.
Subject(s)
Biphenyl Compounds/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Muscarinic Antagonists/chemical synthesis , Tropanes/chemical synthesis , Animals , Biological Availability , Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Bronchi/drug effects , Bronchi/physiology , Bronchoconstriction/drug effects , CHO Cells , Calcium/metabolism , Cricetinae , Cricetulus , Drug Design , Humans , In Vitro Techniques , Mice , Mice, Inbred BALB C , Muscarinic Antagonists/chemistry , Muscarinic Antagonists/pharmacology , Muscle Contraction , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Radioligand Assay , Rats , Receptor, Muscarinic M1/physiology , Receptor, Muscarinic M2/physiology , Receptor, Muscarinic M3/physiology , Stereoisomerism , Structure-Activity Relationship , Tropanes/chemistry , Tropanes/pharmacologyABSTRACT
Design and syntheses of a novel series of muscarinic antagonists are reported. These efforts have culminated in the discovery of (3-endo)-3-(2-cyano-2,2-diphenylethyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane bromide (4a) as a potent and pan-active muscarinic antagonist as well as a functionally active compound in a murine model of bronchoconstriction. The compound has also displayed pharmacokinetic characteristics suitable for inhaled delivery.
Subject(s)
Biphenyl Compounds/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Muscarinic Antagonists/chemistry , Pulmonary Disease, Chronic Obstructive/drug therapy , Receptors, Muscarinic/chemistry , Administration, Inhalation , Animals , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Drug Discovery , Humans , Mice , Muscarinic Antagonists/chemical synthesis , Muscarinic Antagonists/pharmacokinetics , Rats , Receptors, Muscarinic/metabolism , Structure-Activity RelationshipABSTRACT
A novel 4-hydroxyl(diphenyl)methyl substituted quinuclidine series was discovered as a very promising class of muscarinic antagonists. The structure-activity relationships of the connectivity of the diphenyl moiety to the quinuclidine core and around the ring nitrogen side chain are described. Computational docking studies using an homology model of the M(3) receptor readily explained the observed structure-activity relationship of the various compounds. Compound 14o was identified as a very potent, slowly reversible M(3) antagonist with a very long in vivo duration of bronchoprotection.
Subject(s)
Benzhydryl Compounds/chemical synthesis , Bronchodilator Agents/chemical synthesis , Quinuclidines/chemical synthesis , Receptor, Muscarinic M3/antagonists & inhibitors , Animals , Benzhydryl Compounds/chemistry , Benzhydryl Compounds/pharmacology , Biological Availability , Bronchi/drug effects , Bronchi/physiology , Bronchoconstriction/drug effects , Bronchodilator Agents/chemistry , Bronchodilator Agents/pharmacology , CHO Cells , Calcium/metabolism , Cricetinae , Cricetulus , Humans , In Vitro Techniques , Mice , Models, Molecular , Muscle Contraction , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Quinuclidines/chemistry , Quinuclidines/pharmacology , Radioligand Assay , Rats , Structure-Activity RelationshipABSTRACT
A series of novel biphenyl piperazines was discovered as highly potent muscarinic acetylcholine receptor antagonists via high throughput screening and subsequent optimization. Compound 5c with respective 500- and 20-fold subtype selectivity for M3 over M2 and M1 exhibited excellent inhibitory activity and long duration of action in a bronchoconstriction in vivo model in mice via intranasal administration. The novel inhaled mAChR antagonists are potentially useful therapeutic agents for the treatment of chronic obstructive pulmonary disease.
Subject(s)
Bronchoconstriction/drug effects , Bronchodilator Agents/pharmacology , Piperazines/pharmacology , Receptors, Muscarinic/drug effects , Administration, Intranasal , Animals , Bronchial Provocation Tests , Bronchoconstrictor Agents/pharmacology , Bronchodilator Agents/chemical synthesis , Bronchodilator Agents/chemistry , Disease Models, Animal , Drug Evaluation, Preclinical , Methacholine Chloride/pharmacology , Mice , Molecular Structure , Piperazines/chemical synthesis , Piperazines/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
High throughput screening and subsequent optimization led to the discovery of novel quaternary ammonium salts as highly potent muscarinic acetylcholine receptor antagonists with excellent selectivity. Compounds 8a, 13a, and 13b showed excellent inhibitory activity and long duration of action in bronchoconstriction in vivo models in two species via intranasal or intratracheal administration. The novel inhaled muscarinic receptor antagonists are potentially useful therapeutic agents for the treatment of chronic obstructive pulmonary disease and other bronchoconstriction disorders.
Subject(s)
Muscarinic Antagonists/pharmacology , Phenylurea Compounds/pharmacology , Quaternary Ammonium Compounds/pharmacology , Tyrosine/analogs & derivatives , Animals , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Bronchoconstriction/drug effects , Drug Evaluation, Preclinical/methods , Guinea Pigs , Mice , Rats , Tyrosine/pharmacologyABSTRACT
In the course of our research program to develop novel muscarinic receptor antagonists for the treatment of COPD, new tropane carbamate derivatives were identified as potent anti-muscarinic agents. The synthesis, structure-activity relationships and pharmacological evaluation that led to the identification of compound 5o, are described.
