The discovery of long-acting saligenin β2 adrenergic receptor agonists incorporating a urea group

Procopiou, Panayiotis A.; Barrett, Victoria J.; Ford, Alison J.; Looker, Brian E.; Lunniss, Gillian E.; Needham, Deborah; Smith, Claire; Somers, Graham

doi:10.1016/j.bmc.2011.08.043

Cited by 11 publications

(9 citation statements)

References 23 publications

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“…Similar findings were also observed within the salmeterol urea series. 18 The more potent analogue 10c was not investigated any further because of closure of the project.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…It was hypothesized that a polar substituent, such as a sulfone, with high polar surface area and that contravened the Lipinski rules 20 might show reduced oral absorption. Furthermore, we have demonstrated that the introduction of groups such as a sulfonamide, 16 a heterocyclic ring such as hydantoin or uracil 17 or a urea group 18 brought about longer duration of action in addition to reduced oral absorption. The hydantoin ring was, however, found to be unstable both chemically and metabolically and to produce the urea resulting from hydrolysis of the hydantoin ring.…”

Section: Saligenin Analoguesmentioning

confidence: 99%

“…11−13 Furthermore, two reviews on bronchodilators were published recently. 14,15 Our group reported on sulfonamides including GlaxoSmithKline's first candidate 9, 16 on vilanterol (4), 6 on hydantoins, 17 and on urea 18…”

Section: ■ Introductionmentioning

confidence: 99%

“…Other development candidates include Boehringer-Ingelheim’s olodaterol ( 5 ), Pfizer’s candidate PF-610355 ( 6 ), Chiesi’s carmoterol ( 7 ), and Theravance’s milveterol ( 8 ) . In addition further studies were published during the past year describing further compounds at the preclinical stage. − Furthermore, two reviews on bronchodilators were published recently. , Our group reported on sulfonamides including GlaxoSmithKline’s first candidate 9 , on vilanterol ( 4 ), on hydantoins, and on urea saligenin analogues.…”

Section: Introductionmentioning

confidence: 99%

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Discovery of a Rapidly Metabolized, Long-Acting β₂ Adrenergic Receptor Agonist with a Short Onset Time Incorporating a Sulfone Group Suitable for Once-Daily Dosing

et al. 2013

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A series of novel, potent, and selective human β2 adrenoceptor agonists incorporating a sulfone moiety on the terminal right-hand-side phenyl ring of (R)-salmeterol is presented. Sulfone 10b had salmeterol-like potency and selectivity profile, long duration of action on guinea pig trachea, and longer than salmeterol duration of action in vivo, suitable for once-daily dosing. It had lower than salmeterol oral absorption in rat, lower bioavailability in rat and dog, and a high turnover in human hepatocytes. It was metabolized in human hepatocytes by hydroxylation, oxidation, cleavage, and conjugation; most of the metabolites would be expected to have reduced or no β2 activity. The 4-biphenylsulfonic acid was identified as a crystalline, non-hygroscopic salt of 10b, suitable for inhaled delivery. Furthermore, it was free of any genetic toxicity issues and was considered as a backup to vilanterol.

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“…Similar findings were also observed within the salmeterol urea series. 18 The more potent analogue 10c was not investigated any further because of closure of the project.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Saligenin Analoguesmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Discovery of a Rapidly Metabolized, Long-Acting β₂ Adrenergic Receptor Agonist with a Short Onset Time Incorporating a Sulfone Group Suitable for Once-Daily Dosing

et al. 2013

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“…13 Bronchodilators are used for asthma and chronic obstructive pulmonary diseases which are the fourth largest cause of death globally and are expected to be the third largest by 2020 according to World Health Organization reports. 14 X-ray crystallography is a unique technique for 3D-structure studies indicating features hardly determined by other spectroscopic techniques. Accurate knowledge of molecular structures is a prerequisite for rational drug design and structurebased functional studies.…”

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confidence: 99%

Synthesis and X-ray Studies of Novel Azaphenanthrenes

Girgis

Aziz

Shalaby

et al. 2018

Journal of Chemical Research

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Two azaphenanthrenes were synthesised by a facile synthetic pathway and characterised by X-ray crystallography. Molecular packing of 4-(2,4-dichlorophenyl)-2-methoxy-5,6-dihydrobenzo[ h]quinoline-3-carbonitrile exhibits C–H…N and C–H…Cl hydrogen bonds in addition to intermolecular C–H…π, Cl…π and π…π (π-ring) stacking interactions. However, molecules of the 2-ethoxy derivative are linked into chains by one hydrogen bond of the C–H…N type and the crystal structure reveals an intermolecular C–H…π (π-ring) interaction. Computational studies by AM1, PM3, and density functional theory (DFT) techniques provide good approximations to the experimental X-ray data. The root mean square errors between the experimental and calculated bond lengths using AM1, PM3 and DFT methods for the 2-methoxy and 2-ethoxy derivatives are 0.0187, 0.0193, 0.0120 and 0.0197, 0.0195 and 0.0116 respectively.

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Photochemical Synthesis of the Bioactive Fragment of Salbutamol and Derivatives in a Self‐Optimizing Flow Chemistry Platform

Gérardy

Nambiar

Hart

et al. 2022

Chemistry A European J

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The implementation of self‐optimizing flow reactors has been mostly limited to model reactions or known synthesis routes. In this work, a self‐optimizing flow photochemistry platform is used to develop an original synthesis of the bioactive fragment of Salbutamol and derivatives. The key photochemical steps for the construction of the aryl vicinyl amino alcohol moiety consist of a C−C bond forming reaction followed by an unprecedented, high yielding (>80 %), benzylic oxidative cyclization.

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The discovery of long-acting saligenin β2 adrenergic receptor agonists incorporating a urea group

Cited by 11 publications

References 23 publications

Discovery of a Rapidly Metabolized, Long-Acting β₂ Adrenergic Receptor Agonist with a Short Onset Time Incorporating a Sulfone Group Suitable for Once-Daily Dosing

Discovery of a Rapidly Metabolized, Long-Acting β₂ Adrenergic Receptor Agonist with a Short Onset Time Incorporating a Sulfone Group Suitable for Once-Daily Dosing

Synthesis and X-ray Studies of Novel Azaphenanthrenes

Photochemical Synthesis of the Bioactive Fragment of Salbutamol and Derivatives in a Self‐Optimizing Flow Chemistry Platform

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The discovery of long-acting saligenin β2 adrenergic receptor agonists incorporating a urea group

Cited by 11 publications

References 23 publications

Discovery of a Rapidly Metabolized, Long-Acting β2 Adrenergic Receptor Agonist with a Short Onset Time Incorporating a Sulfone Group Suitable for Once-Daily Dosing

Discovery of a Rapidly Metabolized, Long-Acting β2 Adrenergic Receptor Agonist with a Short Onset Time Incorporating a Sulfone Group Suitable for Once-Daily Dosing

Synthesis and X-ray Studies of Novel Azaphenanthrenes

Photochemical Synthesis of the Bioactive Fragment of Salbutamol and Derivatives in a Self‐Optimizing Flow Chemistry Platform

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Product

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Discovery of a Rapidly Metabolized, Long-Acting β₂ Adrenergic Receptor Agonist with a Short Onset Time Incorporating a Sulfone Group Suitable for Once-Daily Dosing

Discovery of a Rapidly Metabolized, Long-Acting β₂ Adrenergic Receptor Agonist with a Short Onset Time Incorporating a Sulfone Group Suitable for Once-Daily Dosing