ABSTRACT
In an attempt to seek increased understanding of compound attributes that influence successful drug pipeline progression, GlaxoSmithKline's portfolio of oral candidates was compared with reference sets of marketed oral drugs. The approach differs from other attrition studies by explicitly focusing on choosing 'the right compound' by applying relevant, experimentally derived properties. The analysis led to four proposed compound quality categories, created by combining specific criteria for three measures: dose, solubility and the property forecast index, a composite measure of lipophilicity using chromatographically determined LogD and aromaticity. The 'three properties' provide benchmarked guidelines for project teams to use when seeking and selecting clinical candidates, because they reflect the property distribution of marketed oral drugs.
Subject(s)
Drug Discovery , Administration, Oral , Animals , Humans , Hydrophobic and Hydrophilic Interactions , Pharmaceutical Preparations/administration & dosage , Pharmaceutical Preparations/chemistry , Pharmaceutical Preparations/metabolism , SolubilityABSTRACT
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
The discovery of potent and selective cyanamide-based inhibitors of the cysteine protease cathepsin C is detailed. Optimization of the template with regard to plasma stability led to the identification of compound 17, a potent cathepsin C inhibitor with excellent selectivity over other cathepsins and potent in vivo activity in a cigarette smoke mouse model.
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
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
SAR exploration of multiple regions of a tyrosine urea template led to the identification of very potent muscarinic acetylcholine receptor antagonists such as 10b with good subtype selectivity for M(3) over M(1). The structure-activity relationships (SAR) and optimization of the tyrosine urea series are described.
Subject(s)
Chemistry, Pharmaceutical/methods , Muscarinic Antagonists/chemical synthesis , Receptors, Muscarinic/chemistry , Tyrosine/chemistry , Urea/chemistry , Asthma/drug therapy , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , Molecular Structure , Muscarinic Antagonists/pharmacology , Salts/chemistry , 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.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Carbamates/chemical synthesis , Muscarinic Antagonists , Receptors, Muscarinic/drug effects , Tropanes/chemical synthesis , Animals , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Bronchodilator Agents/chemical synthesis , Bronchodilator Agents/chemistry , Bronchodilator Agents/pharmacology , Carbamates/chemistry , Carbamates/pharmacology , Drug Evaluation, Preclinical , Inhibitory Concentration 50 , Mice , Molecular Structure , Muscarinic Antagonists/chemical synthesis , Muscarinic Antagonists/chemistry , Muscarinic Antagonists/pharmacology , Pulmonary Disease, Chronic Obstructive/therapy , Tropanes/chemistry , Tropanes/pharmacologyABSTRACT
A series of 3-arylamino-2H-1,2,4-benzothiadiazin-5-ol 1,1-dioxides were prepared and shown to be novel and selective antagonists of the CXCR2 receptor. Synthesis, structure and activity relationships, selectivity, and some developability properties are described.
Subject(s)
Benzothiadiazines/pharmacology , Receptors, Interleukin-8B/antagonists & inhibitors , Benzothiadiazines/chemistry , Structure-Activity RelationshipABSTRACT
N,N'-diarylsquaramides were prepared and evaluated as antagonists of CXCR2. The compounds were found to be potent and selective antagonists of CXCR2. Significant differences in SAR was observed relative to the previously described N,N'-diarylurea series. As was the case in the N,N'-diarylurea series, placing sulfonamide substituent adjacent to the acidic phenol significantly reduced the clearance in rat pharmacokinetic studies.
Subject(s)
Cyclobutanes/chemical synthesis , Cyclobutanes/pharmacology , Cyclobutanes/pharmacokinetics , Receptors, Interleukin-8B/antagonists & inhibitors , Urea/analogs & derivatives , Urea/chemical synthesis , Urea/pharmacology , Urea/pharmacokinetics , Animals , CHO Cells , Chemical Phenomena , Chemistry, Physical , Cricetinae , Cricetulus , Indicators and Reagents , Mass Spectrometry , Phenols/chemistry , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
A series of N-(2-hydroxy-3-sulfonamidobenzene)-N'-arylcyanoguanidines was prepared. In general, these compounds proved to be potent antagonists of CXCR2 while the selectivity versus CXCR1 ranged from non-selective to >200-fold.
Subject(s)
Guanidines/pharmacology , Receptors, Interleukin-8A/antagonists & inhibitors , Receptors, Interleukin-8B/antagonists & inhibitors , Guanidines/chemistry , HumansABSTRACT
The fluorescent styryl dyes FM1-43 and FM2-10 have been used to visualize the endocytic and exocytic processes involved in neurotransmission in a variety of central and peripheral nerve preparations. Their utility is limited to some extent by a poorly understood vesicular-independent labelling of cells and tissues. We show here that one likely cause of this troublesome background labelling is that FM1-43 and FM2-10 are selective and competitive antagonists at both cloned and endogenously expressed muscarinic acetylcholine receptors. In radioligand binding studies, FM1-43 and FM2-10 bound with moderate affinity (23-220 nM) to membranes of Chinese hamster ovary (CHO) cells expressing cloned human muscarinic receptors (M1-M5). In functional studies in vitro, FM1-43 and FM2-10 inhibited electrical field stimulation (EFS) and acetylcholine-induced cholinergic contractions of guinea-pig tracheal strips (IC50: FM1-43, 0.4 +/- 0.1; FM2-10, 1.6 +/- 0.1 microM; concentration of antagonist producing a 2-fold leftward shift in the acetylcholine concentration-response curve (Kb): FM1-43, 0.3 +/- 0.1; FM2-10, 15.8 +/- 10.1 microM). Neither compound inhibited EFS-evoked, non-adrenergic non-cholinergic nerve-mediated relaxations or contractions of the airways, or contractions mediated by histamine H1 receptor or tachykinin NK2 receptor activation. Incubating freshly excised tracheal whole-mount preparations with 5 microM FM1-43 resulted in intense fluorescence labelling of the smooth muscle that was reduced by up to 90% in the presence of selective M2 and M3 receptor antagonists. The potency of the FM dyes as muscarinic receptor antagonists is within the concentration range used to study vesicular cycling at nerve terminals. Given that muscarinic receptors play a key role in the regulation of neurotransmitter release from a variety of neurones, the anticholinergic properties of FM dyes may have important implications when studying vesicular events in the nervous system. In addition, these dyes may provide a novel tool for visualizing muscarinic receptor occupancy in living tissue or cell preparations.
Subject(s)
Fluorescent Dyes/metabolism , Muscarinic Antagonists/metabolism , Pyridinium Compounds/metabolism , Quaternary Ammonium Compounds/metabolism , Receptors, Muscarinic/metabolism , Animals , CHO Cells , Cricetinae , Cricetulus , Dose-Response Relationship, Drug , Fluorescent Dyes/pharmacology , Guinea Pigs , Male , Muscarinic Antagonists/pharmacology , Muscle Contraction , Muscle, Smooth/drug effects , Pyridinium Compounds/pharmacology , Quaternary Ammonium Compounds/pharmacology , Receptors, Muscarinic/drug effects , Receptors, Muscarinic/genetics , Staining and Labeling/methods , Trachea/drug effects , TransfectionABSTRACT
A series of 3-substituted N,N'-diarylureas was prepared and the structure-activity relationship relative to CXCR2 receptor affinity as well as their pharmacokinetic properties were examined. In vitro microsomal metabolism studies indicated that the lower clearance rates of the 3-sulfonamido-substituted compounds were most likely due to the suppression of glucuronidation.
