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
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
In 2002, the first long-acting muscarinic antagonist, tiotropium bromide (Spiriva(®)), was launched as a once-daily bronchodilating agent for the treatment of chronic obstructive pulmonary disease. Since then, there has been intense discovery research activity in this area and, currently, several alternative inhaled long-acting muscarinic antagonists are reported under clinical development by several pharmaceutical companies. This article will review the current inhaled development candidates, as well as literature reports of the most significant preclinical chemical series specifically designed as inhaled antimuscarinic agents.
Subject(s)
Bronchodilator Agents/therapeutic use , Muscarinic Antagonists/therapeutic use , Pulmonary Disease, Chronic Obstructive/drug therapy , Administration, Inhalation , Bronchodilator Agents/administration & dosage , Humans , Molecular Weight , Muscarinic Antagonists/administration & dosageABSTRACT
IMPORTANCE TO THE FIELD: Cathepsin C (dipeptidyl peptidase I) plays a key role in the activation of several degradative enzymes linked to tissue destruction in inflammatory diseases. Thus, cathepsin C inhibitors could potentially be effective therapeutics for the treatment of such diseases as chronic obstructive pulmonary disease and cystic fibrosis. AREAS COVERED IN THIS REVIEW: Although this article focuses on cathepsin C inhibitor patents, the journal literature concerning small molecule inhibitors of the enzyme is also covered comprehensively (1981 - 2009). WHAT THE READER WILL GAIN: It is our aim to give the reader a complete overview of the cathepsin C inhibitor chemotypes that have been disclosed to date. In addition, key biological data have been included for both irreversible and reversible inhibitors. TAKE HOME MESSAGE: All known cathepsin C inhibitors are believed to have a covalent interaction with the Cys-234 residue of the enzyme. The electrophilic and sometimes peptidic nature of these molecules is associated with poor metabolic stability and is also a potential safety concern. Thus, overcoming developability issues is a serious hurdle for these compounds and there can be little doubt that this is the principal reason why no cathepsin C inhibitors appear to have reached clinical development so far.
Subject(s)
Cathepsin C/antagonists & inhibitors , Cystic Fibrosis/drug therapy , Pulmonary Disease, Chronic Obstructive/drug therapy , Animals , Cystic Fibrosis/enzymology , Cystic Fibrosis/physiopathology , Drug Design , Humans , Inflammation/drug therapy , Inflammation/enzymology , Inflammation/physiopathology , Patents as Topic , Pulmonary Disease, Chronic Obstructive/enzymology , Pulmonary Disease, Chronic Obstructive/physiopathologyABSTRACT
Muscarinic acetylcholine receptor antagonists, particularly of the M(3) subtype, are useful therapeutics as bronchodilators in chronic obstructive pulmonary disease (COPD). The first long-acting muscarinic antagonist, tiotropium bromide (Spiriva(®)), was launched in 2002 and has since become established as the gold-standard muscarinic antagonist for the treatment of COPD. This review will survey the preclinical profiles of tiotropium and nine inhaled development candidates as well as literature reports of other preclinical compounds specifically designed as inhaled antimuscarinic agents for the treatment of COPD. The design strategies employed lay behind three common principles: high potency and slow reversibility at the M(3) receptor and low systemic exposure. In addition to their effectiveness as bronchodilators, the differentiation of these agents in the clinic may be linked to their potential to be utilized in combination with other therapeutics. In the long term, the emerging knowledge around the role of muscarinic antagonists in the inflammation and remodeling of the airways may also help in discriminating them.
ABSTRACT
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 short synthesis of the non-adjacent bis-THF core of the Annonaceous acetogenin cis-sylvaticin (1) is described. C(2) Symmetrical (Z,E,E,Z)- and (E,E,E,E)-tetraenes and were synthesised in six and three steps respectively from (1E,5E,9E)-cyclododeca-1,5,9-triene. Subsequent permanganate promoted asymmetric bi-directional oxidative cyclisation of tetraene was used to create the non-adjacent bis-THF core of 1, installing seven of the nine stereogenic centres present in the natural product in a single step. Desymmetrization of the oxidative cyclisation product by mono-tosylation gave access to a C11-C32 fragment of cis-sylvaticin.
Subject(s)
Furans/chemistry , Cyclization , Furans/chemical synthesis , Oxidation-Reduction , Polyenes/chemistry , StereoisomerismABSTRACT
Exploration of multiple regions of a bi-aryl amine template led to the identification of highly potent M(3) muscarinic acetylcholine receptor antagonists such as 14 (pA(2)=11.0) possessing good sub-type selectivity for M(3) over M(2). The structure-activity relationships (SAR) and optimization of the bi-aryl amine series are described.
Subject(s)
Amines/chemical synthesis , Chemistry, Pharmaceutical/methods , Receptor, Muscarinic M3/antagonists & inhibitors , Amides/chemistry , Amines/pharmacology , Asthma/drug therapy , Drug Design , Electrons , Humans , Inhibitory Concentration 50 , Kinetics , Models, Chemical , Molecular Structure , Pulmonary Disease, Chronic Obstructive/drug therapy , Receptor, Muscarinic M3/chemistry , 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
The biphenyl amides (BPAs) are a series of p38alpha MAP kinase inhibitors. Compounds are able to bind to the kinase in either the DFG-in or DFG-out conformation, depending on substituents. X-ray, binding, kinetic and cellular data are shown, providing the most detailed comparison to date between potent compounds from the same chemical series that bind to different p38alpha conformations. DFG-out-binding compounds could be made more potent than DFG-in-binding compounds by increasing their size. Unexpectedly, compounds that bound to the DGF-out conformation showed diminished selectivity. The kinetics of binding to the isolated enzyme and the effects of compounds on cells were largely unaffected by the kinase conformation bound.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/pharmacology , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Amides/blood , Amides/chemistry , Amino Acids/genetics , Amino Acids/metabolism , Binding Sites , Biphenyl Compounds/blood , Biphenyl Compounds/chemistry , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Drug Design , Lipopolysaccharides/pharmacology , Molecular Conformation , Molecular Structure , Naphthalenes/pharmacology , Pyrazoles/pharmacology , Structure-Activity RelationshipABSTRACT
The biphenyl amides (BPAs) are a novel series of p38alpha MAP kinase inhibitor. The optimisation of the series to give compounds that are potent in an in vivo disease model is discussed. SAR is presented and rationalised with reference to the crystallographic binding mode.
Subject(s)
Benzamides/chemical synthesis , Benzamides/pharmacology , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/pharmacology , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Administration, Oral , Animals , Benzamides/blood , Benzamides/chemistry , Biphenyl Compounds/blood , Biphenyl Compounds/chemistry , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Disease Models, Animal , Molecular Conformation , Molecular Structure , Protein Kinase Inhibitors/blood , Protein Kinase Inhibitors/chemistry , RatsABSTRACT
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.