The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Panayiotis A Procopiou - One of the best experts on this subject based on the ideXlab platform.
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the discovery of long acting Saligenin β adrenergic receptor agonists incorporating a urea group
Bioorganic & Medicinal Chemistry, 2011Co-Authors: Panayiotis A Procopiou, Victoria J Barrett, Alison J Ford, Brian Edgar Looker, Gillian Elizabeth Lunniss, Deborah Needham, Claire E Smith, Graham SomersAbstract:A series of novel, potent and selective human β(2) adrenoceptor agonists incorporating a urea moiety on the terminal right-hand side phenyl ring of (R)-salmeterol is presented. Urea 9j had long duration of action in vitro on guinea pig trachea, and also in vivo similar to that of salmeterol. It had lower oral absorption and bioavailability than salmeterol in both rat and dog. It had a turnover ratio similar to salmeterol, with no evidence for formation of any aniline metabolites in human liver microsomes and hepatocytes. However no crystalline salts suitable for inhaled delivery were identified.
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the discovery of long acting Saligenin β2 adrenergic receptor agonists incorporating hydantoin or uracil rings
Bioorganic & Medicinal Chemistry, 2011Co-Authors: Panayiotis A Procopiou, Victoria J Barrett, Nicola Bevan, Peter R Butchers, Richard Conroy, Amanda Emmons, Alison J Ford, Severine Jeulin, Brian Edgar Looker, Gillian Elizabeth LunnissAbstract:Abstract A series of novel, potent and selective human β 2 adrenoceptor agonists incorporating a hydantoin or a uracil ring on the right-hand side phenyl ring of ( R )-salmeterol is presented. Hydantoin 12a had long duration of action in vitro on guinea pig trachea, and 12 h in guinea pigs in vivo at its EC 90 25 μM. It had lower oral absorption than salmeterol in rats, and lower bioavailability than salmeterol in vivo in both rats and dogs (2% and 5%, respectively). An improved method for measuring the absorbed fraction of analogues dosed to rats, which considers the glucuronidated fraction is presented. Compound 12a was metabolised in human liver microsomes and hepatocytes to the active hydantoic acid 12m .
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synthesis and structure activity relationships of long acting β2 adrenergic receptor agonists incorporating metabolic inactivation an antedrug approach
Journal of Medicinal Chemistry, 2010Co-Authors: Panayiotis A Procopiou, Victoria J Barrett, Nicola Bevan, Peter R Butchers, Richard Conroy, Amanda Emmons, Alison J Ford, Keith Biggadike, Duncan S Holmes, Helen Tracey HorsleyAbstract:A series of Saligenin β2 adrenoceptor agonist antedrugs having high clearance were prepared by reacting a protected Saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of the hydroxy-protecting group, alkylation, and final deprotection. The compounds were screened for β2, β1, and β3 agonist activity in CHO cells. The onset and duration of action in vitro of selected compounds were assessed on isolated superfused guinea pig trachea. Compound 13f had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo, low oral bioavailability in the rat, and to be rapidly metabolized. Crystalline salts of 13f (vilanterol) were identified that had suitable properties for inhaled administration. A proposed binding mode for 13f to the β2-receptor is presented.
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synthesis and structure activity relationships of long acting β2 adrenergic receptor agonists incorporating arylsulfonamide groups
Journal of Medicinal Chemistry, 2009Co-Authors: Panayiotis A Procopiou, Victoria J Barrett, Nicola Bevan, Peter R Butchers, Richard Conroy, Keith Biggadike, Diane Mary Coe, Dean David Edney, Rita Field, Alison J FordAbstract:A series of Saligenin alkoxyalkylphenylsulfonamide β2 adrenoceptor agonists were prepared by reacting a protected Saligenin oxazolidinone with alkynyloxyalkyl bromides, followed by Sonogashira reaction, hydrogenation, and deprotection. The meta-substituted primary sulfonamide was more potent than the para- and the ortho-analogues. Primary sulfonamides were more potent than the secondary and tertiary analogues. The onset and duration of action in vitro of selected compounds was assessed on isolated superfused guinea pig trachea. Sulfonamide 29b had the best profile of potency, selectivity, onset, and duration of action on both guinea pig trachea and human bronchus. Furthermore, 29b was found to have low oral bioavailability in rat and dog and also to have long duration of action in an in vivo model of bronchodilation. Crystalline salts of 29b were identified that had suitable properties for inhaled administration. A proposed binding mode for 29b to the β2-receptor is presented.
Alison J Ford - One of the best experts on this subject based on the ideXlab platform.
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the discovery of long acting Saligenin β adrenergic receptor agonists incorporating a urea group
Bioorganic & Medicinal Chemistry, 2011Co-Authors: Panayiotis A Procopiou, Victoria J Barrett, Alison J Ford, Brian Edgar Looker, Gillian Elizabeth Lunniss, Deborah Needham, Claire E Smith, Graham SomersAbstract:A series of novel, potent and selective human β(2) adrenoceptor agonists incorporating a urea moiety on the terminal right-hand side phenyl ring of (R)-salmeterol is presented. Urea 9j had long duration of action in vitro on guinea pig trachea, and also in vivo similar to that of salmeterol. It had lower oral absorption and bioavailability than salmeterol in both rat and dog. It had a turnover ratio similar to salmeterol, with no evidence for formation of any aniline metabolites in human liver microsomes and hepatocytes. However no crystalline salts suitable for inhaled delivery were identified.
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the discovery of long acting Saligenin β2 adrenergic receptor agonists incorporating hydantoin or uracil rings
Bioorganic & Medicinal Chemistry, 2011Co-Authors: Panayiotis A Procopiou, Victoria J Barrett, Nicola Bevan, Peter R Butchers, Richard Conroy, Amanda Emmons, Alison J Ford, Severine Jeulin, Brian Edgar Looker, Gillian Elizabeth LunnissAbstract:Abstract A series of novel, potent and selective human β 2 adrenoceptor agonists incorporating a hydantoin or a uracil ring on the right-hand side phenyl ring of ( R )-salmeterol is presented. Hydantoin 12a had long duration of action in vitro on guinea pig trachea, and 12 h in guinea pigs in vivo at its EC 90 25 μM. It had lower oral absorption than salmeterol in rats, and lower bioavailability than salmeterol in vivo in both rats and dogs (2% and 5%, respectively). An improved method for measuring the absorbed fraction of analogues dosed to rats, which considers the glucuronidated fraction is presented. Compound 12a was metabolised in human liver microsomes and hepatocytes to the active hydantoic acid 12m .
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synthesis and structure activity relationships of long acting β2 adrenergic receptor agonists incorporating metabolic inactivation an antedrug approach
Journal of Medicinal Chemistry, 2010Co-Authors: Panayiotis A Procopiou, Victoria J Barrett, Nicola Bevan, Peter R Butchers, Richard Conroy, Amanda Emmons, Alison J Ford, Keith Biggadike, Duncan S Holmes, Helen Tracey HorsleyAbstract:A series of Saligenin β2 adrenoceptor agonist antedrugs having high clearance were prepared by reacting a protected Saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of the hydroxy-protecting group, alkylation, and final deprotection. The compounds were screened for β2, β1, and β3 agonist activity in CHO cells. The onset and duration of action in vitro of selected compounds were assessed on isolated superfused guinea pig trachea. Compound 13f had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo, low oral bioavailability in the rat, and to be rapidly metabolized. Crystalline salts of 13f (vilanterol) were identified that had suitable properties for inhaled administration. A proposed binding mode for 13f to the β2-receptor is presented.
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synthesis and structure activity relationships of long acting β2 adrenergic receptor agonists incorporating arylsulfonamide groups
Journal of Medicinal Chemistry, 2009Co-Authors: Panayiotis A Procopiou, Victoria J Barrett, Nicola Bevan, Peter R Butchers, Richard Conroy, Keith Biggadike, Diane Mary Coe, Dean David Edney, Rita Field, Alison J FordAbstract:A series of Saligenin alkoxyalkylphenylsulfonamide β2 adrenoceptor agonists were prepared by reacting a protected Saligenin oxazolidinone with alkynyloxyalkyl bromides, followed by Sonogashira reaction, hydrogenation, and deprotection. The meta-substituted primary sulfonamide was more potent than the para- and the ortho-analogues. Primary sulfonamides were more potent than the secondary and tertiary analogues. The onset and duration of action in vitro of selected compounds was assessed on isolated superfused guinea pig trachea. Sulfonamide 29b had the best profile of potency, selectivity, onset, and duration of action on both guinea pig trachea and human bronchus. Furthermore, 29b was found to have low oral bioavailability in rat and dog and also to have long duration of action in an in vivo model of bronchodilation. Crystalline salts of 29b were identified that had suitable properties for inhaled administration. A proposed binding mode for 29b to the β2-receptor is presented.
Alan J Hargreaves - One of the best experts on this subject based on the ideXlab platform.
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phenyl Saligenin phosphate induced caspase 3 and c jun n terminal kinase activation in cardiomyocyte like cells
Chemical Research in Toxicology, 2015Co-Authors: Shatha G. Felemban, Alan J Hargreaves, Fathi A. Smida, David J. Boocock, A C Garner, John M. DickensonAbstract:At present, little is known about the effect(s) of organophosphorous compounds (OPs) on cardiomyocytes. In this study, we have investigated the effects of phenyl Saligenin phosphate (PSP), two organophosphorothioate insecticides (diazinon and chlorpyrifos), and their acutely toxic metabolites (diazoxon and chlorpyrifos oxon) on mitotic and differentiated H9c2 cardiomyoblasts. OP-induced cytotoxicity was assessed by monitoring MTT reduction, LDH release, and caspase-3 activity. Cytotoxicity was not observed with diazinon, diazoxon, or chlorpyrifos oxon (48 h exposure; 200 μM). Chlorpyrifos-induced cytotoxicity was only evident at concentrations >100 μM. In marked contrast, PSP displayed pronounced cytotoxicity toward mitotic and differentiated H9c2 cells. PSP triggered the activation of JNK1/2 but not ERK1/2, p38 MAPK, or PKB, suggesting a role for this pro-apoptotic protein kinase in PSP-induced cell death. The JNK1/2 inhibitor SP 600125 attenuated PSP-induced caspase-3 and JNK1/2 activation, confirming the role of JNK1/2 in PSP-induced cytotoxicity. Fluorescently labeled PSP (dansylated PSP) was used to identify novel PSP binding proteins. Dansylated PSP displayed cytotoxicity toward differentiated H9c2 cells. 2D-gel electrophoresis profiles of cells treated with dansylated PSP (25 μM) were used to identify proteins fluorescently labeled with dansylated PSP. Proteomic analysis identified tropomyosin, heat shock protein β-1, and nucleolar protein 58 as novel protein targets for PSP. In summary, PSP triggers cytotoxicity in differentiated H9c2 cardiomyoblasts via JNK1/2-mediated activation of caspase-3. Further studies are required to investigate whether the identified novel protein targets of PSP play a role in the cytotoxicity of this OP, which is usually associated with the development of OP-induced delayed neuropathy.
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phenyl Saligenin phosphate induced caspase 3 and c jun n terminal kinase activation in cardiomyocyte like cells
Chemical Research in Toxicology, 2015Co-Authors: Shatha G. Felemban, Alan J Hargreaves, David J. Boocock, A C Garner, Fa Smida, John M. DickensonAbstract:At present, little is known about the effect(s) of organophosphorous compounds (OPs) on cardiomyocytes. In this study, we have investigated the effects of phenyl Saligenin phosphate (PSP), two organophosphorothioate insecticides (diazinon and chlorpyrifos), and their acutely toxic metabolites (diazoxon and chlorpyrifos oxon) on mitotic and differentiated H9c2 cardiomyoblasts. OP-induced cytotoxicity was assessed by monitoring MTT reduction, LDH release, and caspase-3 activity. Cytotoxicity was not observed with diazinon, diazoxon, or chlorpyrifos oxon (48 h exposure; 200 μM). Chlorpyrifos-induced cytotoxicity was only evident at concentrations >100 μM. In marked contrast, PSP displayed pronounced cytotoxicity toward mitotic and differentiated H9c2 cells. PSP triggered the activation of JNK1/2 but not ERK1/2, p38 MAPK, or PKB, suggesting a role for this pro-apoptotic protein kinase in PSP-induced cell death. The JNK1/2 inhibitor SP 600125 attenuated PSP-induced caspase-3 and JNK1/2 activation, confirming t...
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Phenyl Saligenin Phosphate Induced Caspase‑3 and c‑Jun N‑Terminal Kinase Activation in Cardiomyocyte-Like Cells
2015Co-Authors: Shatha G. Felemban, Alan J Hargreaves, Christopher A. Garner, Fathi A. Smida, David J. Boocock, John M. DickensonAbstract:At present, little is known about the effect(s) of organophosphorous compounds (OPs) on cardiomyocytes. In this study, we have investigated the effects of phenyl Saligenin phosphate (PSP), two organophosphorothioate insecticides (diazinon and chlorpyrifos), and their acutely toxic metabolites (diazoxon and chlorpyrifos oxon) on mitotic and differentiated H9c2 cardiomyoblasts. OP-induced cytotoxicity was assessed by monitoring MTT reduction, LDH release, and caspase-3 activity. Cytotoxicity was not observed with diazinon, diazoxon, or chlorpyrifos oxon (48 h exposure; 200 μM). Chlorpyrifos-induced cytotoxicity was only evident at concentrations >100 μM. In marked contrast, PSP displayed pronounced cytotoxicity toward mitotic and differentiated H9c2 cells. PSP triggered the activation of JNK1/2 but not ERK1/2, p38 MAPK, or PKB, suggesting a role for this pro-apoptotic protein kinase in PSP-induced cell death. The JNK1/2 inhibitor SP 600125 attenuated PSP-induced caspase-3 and JNK1/2 activation, confirming the role of JNK1/2 in PSP-induced cytotoxicity. Fluorescently labeled PSP (dansylated PSP) was used to identify novel PSP binding proteins. Dansylated PSP displayed cytotoxicity toward differentiated H9c2 cells. 2D-gel electrophoresis profiles of cells treated with dansylated PSP (25 μM) were used to identify proteins fluorescently labeled with dansylated PSP. Proteomic analysis identified tropomyosin, heat shock protein β-1, and nucleolar protein 58 as novel protein targets for PSP. In summary, PSP triggers cytotoxicity in differentiated H9c2 cardiomyoblasts via JNK1/2-mediated activation of caspase-3. Further studies are required to investigate whether the identified novel protein targets of PSP play a role in the cytotoxicity of this OP, which is usually associated with the development of OP-induced delayed neuropathy
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effects of phenyl Saligenin phosphate on cell viability and transglutaminase activity in n2a neuroblastoma and hepg2 hepatoma cell lines
Toxicology in Vitro, 2009Co-Authors: Wayne Harris, D Munoz, Philip L R Bonner, Alan J HargreavesAbstract:Abstract The main aim of this study was to determine whether sub-lethal concentrations of the organophosphate compound phenyl Saligenin phosphate (PSP) could disrupt the activity of the Ca 2+ -activated enzyme tissue transglutaminase (TGase 2) from cultured cell lines of neuronal (N2a) and hepatic (HepG2) origin. The results indicated that PSP added directly to cytosol extracts from healthy cells was able to inhibit TGase 2 activity by 40–60% of control levels at sub-lethal concentrations (⩾0.1 μM) that were approximately 100-fold lower than their IC 50 values in cytotoxicity assays. Following 24 h exposure of N2a cells to 0.3 and 3 μM PSP in situ , a similar reduction in activity was observed in subsequent assays of TGase 2 activity. However, significantly increased activity was observed following in situ exposure of HepG2 cells to PSP (ca. 4-fold at 3 μM). Western blotting analysis indicated slightly reduced levels of TGase 2 in N2a cells compared to the control, whereas an increase was observed in the level of TGase 2 in HepG2 cells. We suggest that TGase 2 represents a potential target of organophosphate toxicity and that its response may vary in different cellular environments, possibly affected by its expression pattern.
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effects of phenyl Saligenin phosphate on phosphorylation of pig brain tubulin in vitro
Environmental Toxicology and Pharmacology, 2006Co-Authors: John Flaskos, Magdalini Sachana, Wayne Harris, Michele Pen, Alan J HargreavesAbstract:Phenyl Saligenin phosphate (PSP) induces a characteristic neuropathy (OPIDN), the molecular basis of which has not been precisely defined. This study examined the in vitro effects of PSP on the phosphorylation of serine and threonine residues of proteins in porcine brain cytosol. Quantitative analysis of Western blots probed with antibodies recognizing phosphorylated serine residues demonstrated that 100μM PSP induced a significant increase in the phosphorylation of serine residues of a 50kDa protein. This protein was identified as the α- and β-tubulin subunits by probing Western blots of extracts separated by two-dimensional polyacrylamide gel electrophoresis with anti-phosphoserine and anti-tubulin antibodies. By contrast, threonine phosphorylation of the 50kDa polypeptide and other proteins detected on Western blots probed with anti-phosphothreonine antibodies, was not significantly affected by PSP. These data indicate that PSP is able to induce increased phosphorylation of tubulin in serine residues, consistent with a possible role for this phenomenon in OPIDN induction.
Victoria J Barrett - One of the best experts on this subject based on the ideXlab platform.
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the discovery of long acting Saligenin β adrenergic receptor agonists incorporating a urea group
Bioorganic & Medicinal Chemistry, 2011Co-Authors: Panayiotis A Procopiou, Victoria J Barrett, Alison J Ford, Brian Edgar Looker, Gillian Elizabeth Lunniss, Deborah Needham, Claire E Smith, Graham SomersAbstract:A series of novel, potent and selective human β(2) adrenoceptor agonists incorporating a urea moiety on the terminal right-hand side phenyl ring of (R)-salmeterol is presented. Urea 9j had long duration of action in vitro on guinea pig trachea, and also in vivo similar to that of salmeterol. It had lower oral absorption and bioavailability than salmeterol in both rat and dog. It had a turnover ratio similar to salmeterol, with no evidence for formation of any aniline metabolites in human liver microsomes and hepatocytes. However no crystalline salts suitable for inhaled delivery were identified.
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the discovery of long acting Saligenin β2 adrenergic receptor agonists incorporating hydantoin or uracil rings
Bioorganic & Medicinal Chemistry, 2011Co-Authors: Panayiotis A Procopiou, Victoria J Barrett, Nicola Bevan, Peter R Butchers, Richard Conroy, Amanda Emmons, Alison J Ford, Severine Jeulin, Brian Edgar Looker, Gillian Elizabeth LunnissAbstract:Abstract A series of novel, potent and selective human β 2 adrenoceptor agonists incorporating a hydantoin or a uracil ring on the right-hand side phenyl ring of ( R )-salmeterol is presented. Hydantoin 12a had long duration of action in vitro on guinea pig trachea, and 12 h in guinea pigs in vivo at its EC 90 25 μM. It had lower oral absorption than salmeterol in rats, and lower bioavailability than salmeterol in vivo in both rats and dogs (2% and 5%, respectively). An improved method for measuring the absorbed fraction of analogues dosed to rats, which considers the glucuronidated fraction is presented. Compound 12a was metabolised in human liver microsomes and hepatocytes to the active hydantoic acid 12m .
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synthesis and structure activity relationships of long acting β2 adrenergic receptor agonists incorporating metabolic inactivation an antedrug approach
Journal of Medicinal Chemistry, 2010Co-Authors: Panayiotis A Procopiou, Victoria J Barrett, Nicola Bevan, Peter R Butchers, Richard Conroy, Amanda Emmons, Alison J Ford, Keith Biggadike, Duncan S Holmes, Helen Tracey HorsleyAbstract:A series of Saligenin β2 adrenoceptor agonist antedrugs having high clearance were prepared by reacting a protected Saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of the hydroxy-protecting group, alkylation, and final deprotection. The compounds were screened for β2, β1, and β3 agonist activity in CHO cells. The onset and duration of action in vitro of selected compounds were assessed on isolated superfused guinea pig trachea. Compound 13f had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo, low oral bioavailability in the rat, and to be rapidly metabolized. Crystalline salts of 13f (vilanterol) were identified that had suitable properties for inhaled administration. A proposed binding mode for 13f to the β2-receptor is presented.
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synthesis and structure activity relationships of long acting β2 adrenergic receptor agonists incorporating arylsulfonamide groups
Journal of Medicinal Chemistry, 2009Co-Authors: Panayiotis A Procopiou, Victoria J Barrett, Nicola Bevan, Peter R Butchers, Richard Conroy, Keith Biggadike, Diane Mary Coe, Dean David Edney, Rita Field, Alison J FordAbstract:A series of Saligenin alkoxyalkylphenylsulfonamide β2 adrenoceptor agonists were prepared by reacting a protected Saligenin oxazolidinone with alkynyloxyalkyl bromides, followed by Sonogashira reaction, hydrogenation, and deprotection. The meta-substituted primary sulfonamide was more potent than the para- and the ortho-analogues. Primary sulfonamides were more potent than the secondary and tertiary analogues. The onset and duration of action in vitro of selected compounds was assessed on isolated superfused guinea pig trachea. Sulfonamide 29b had the best profile of potency, selectivity, onset, and duration of action on both guinea pig trachea and human bronchus. Furthermore, 29b was found to have low oral bioavailability in rat and dog and also to have long duration of action in an in vivo model of bronchodilation. Crystalline salts of 29b were identified that had suitable properties for inhaled administration. A proposed binding mode for 29b to the β2-receptor is presented.
Peter R Butchers - One of the best experts on this subject based on the ideXlab platform.
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the discovery of long acting Saligenin β2 adrenergic receptor agonists incorporating hydantoin or uracil rings
Bioorganic & Medicinal Chemistry, 2011Co-Authors: Panayiotis A Procopiou, Victoria J Barrett, Nicola Bevan, Peter R Butchers, Richard Conroy, Amanda Emmons, Alison J Ford, Severine Jeulin, Brian Edgar Looker, Gillian Elizabeth LunnissAbstract:Abstract A series of novel, potent and selective human β 2 adrenoceptor agonists incorporating a hydantoin or a uracil ring on the right-hand side phenyl ring of ( R )-salmeterol is presented. Hydantoin 12a had long duration of action in vitro on guinea pig trachea, and 12 h in guinea pigs in vivo at its EC 90 25 μM. It had lower oral absorption than salmeterol in rats, and lower bioavailability than salmeterol in vivo in both rats and dogs (2% and 5%, respectively). An improved method for measuring the absorbed fraction of analogues dosed to rats, which considers the glucuronidated fraction is presented. Compound 12a was metabolised in human liver microsomes and hepatocytes to the active hydantoic acid 12m .
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synthesis and structure activity relationships of long acting β2 adrenergic receptor agonists incorporating metabolic inactivation an antedrug approach
Journal of Medicinal Chemistry, 2010Co-Authors: Panayiotis A Procopiou, Victoria J Barrett, Nicola Bevan, Peter R Butchers, Richard Conroy, Amanda Emmons, Alison J Ford, Keith Biggadike, Duncan S Holmes, Helen Tracey HorsleyAbstract:A series of Saligenin β2 adrenoceptor agonist antedrugs having high clearance were prepared by reacting a protected Saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of the hydroxy-protecting group, alkylation, and final deprotection. The compounds were screened for β2, β1, and β3 agonist activity in CHO cells. The onset and duration of action in vitro of selected compounds were assessed on isolated superfused guinea pig trachea. Compound 13f had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo, low oral bioavailability in the rat, and to be rapidly metabolized. Crystalline salts of 13f (vilanterol) were identified that had suitable properties for inhaled administration. A proposed binding mode for 13f to the β2-receptor is presented.
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synthesis and structure activity relationships of long acting β2 adrenergic receptor agonists incorporating arylsulfonamide groups
Journal of Medicinal Chemistry, 2009Co-Authors: Panayiotis A Procopiou, Victoria J Barrett, Nicola Bevan, Peter R Butchers, Richard Conroy, Keith Biggadike, Diane Mary Coe, Dean David Edney, Rita Field, Alison J FordAbstract:A series of Saligenin alkoxyalkylphenylsulfonamide β2 adrenoceptor agonists were prepared by reacting a protected Saligenin oxazolidinone with alkynyloxyalkyl bromides, followed by Sonogashira reaction, hydrogenation, and deprotection. The meta-substituted primary sulfonamide was more potent than the para- and the ortho-analogues. Primary sulfonamides were more potent than the secondary and tertiary analogues. The onset and duration of action in vitro of selected compounds was assessed on isolated superfused guinea pig trachea. Sulfonamide 29b had the best profile of potency, selectivity, onset, and duration of action on both guinea pig trachea and human bronchus. Furthermore, 29b was found to have low oral bioavailability in rat and dog and also to have long duration of action in an in vivo model of bronchodilation. Crystalline salts of 29b were identified that had suitable properties for inhaled administration. A proposed binding mode for 29b to the β2-receptor is presented.
