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12 results on '"Adam J. Davenport"'

1. Eliapixant is a selective P2X3 receptor antagonist for the treatment of disorders associated with hypersensitive nerve fibers

Author

Adam J. Davenport, Ioana Neagoe, Nico Bräuer, Markus Koch, Andrea Rotgeri, Jens Nagel, Alexis Laux-Biehlmann, Frederic Machet, Anne-Marie Coelho, Susan Boyce, Nikisha Carty, Mark J. Gemkow, Stephen D. Hess, Thomas M. Zollner, and Oliver M. Fischer

Subjects
Medicine, Science
Abstract

Abstract ATP-dependent P2X3 receptors play a crucial role in the sensitization of nerve fibers and pathological pain pathways. They are also involved in pathways triggering cough and may contribute to the pathophysiology of endometriosis and overactive bladder. However, despite the strong therapeutic rationale for targeting P2X3 receptors, preliminary antagonists have been hampered by off-target effects, including severe taste disturbances associated with blocking the P2X2/3 receptor heterotrimer. Here we present a P2X3 receptor antagonist, eliapixant (BAY 1817080), which is both highly potent and selective for P2X3 over other P2X subtypes in vitro, including P2X2/3. We show that eliapixant reduces inflammatory pain in relevant animal models. We also provide the first in vivo experimental evidence that P2X3 antagonism reduces neurogenic inflammation, a phenomenon hypothesised to contribute to several diseases, including endometriosis. To test whether eliapixant could help treat endometriosis, we confirmed P2X3 expression on nerve fibers innervating human endometriotic lesions. We then demonstrate that eliapixant reduces vaginal hyperalgesia in an animal model of endometriosis-associated dyspareunia, even beyond treatment cessation. Our findings indicate that P2X3 antagonism could alleviate pain, including non-menstrual pelvic pain, and modify the underlying disease pathophysiology in women with endometriosis. Eliapixant is currently under clinical development for the treatment of disorders associated with hypersensitive nerve fibers.

Published
2021
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2. Chiral pyridine imidazolines from C1-symmetric diamines: Synthesis, arene ruthenium complexes and application as asymmetric catalysis for Diels-Alder reactions

Author

David L. Davies, Adam J. Davenport, David R. Russell, and John Fawcett

Subjects
Cyclopentadiene, Organic Chemistry, Ethylenediamines, Enantioselective synthesis, chemistry.chemical_element, Methacrolein, Oxazoline, Biochemistry, Medicinal chemistry, Catalysis, Ruthenium, Inorganic Chemistry, chemistry.chemical_compound, chemistry, Pyridine, Materials Chemistry, Organic chemistry, Physical and Theoretical Chemistry
Abstract

Condensation of mono N-substituted chiral ethylenediamines and pyridine-2-methoxyimidate gives new chiral pyridine imidazolines ( 1a – c ). These react with [RuCl 2 (mes)] 2 (mes = 1,3,5-trimethyl benzene) in the presence of NaSbF 6 to give complexes [RuCl(L)(mes)][SbF 6 ] ( 5a – c ) which after treatment with AgSbF 6 are enantioselective catalysts for the Diels-Alder reaction of methacrolein and cyclopentadiene. The imidazoline catalysts are less selective than the corresponding oxazoline ones. Compounds 1a , 5b and 5c have been characterised by X-ray crystallography.

Published
2006

3. Cp*rhodium complexes with salicyloxazolines: Diastereoselective synthesis, configurational stability and use as asymmetric catalysts for a Diels–Alder reaction

Author

David L. Davies, David R. Russell, John Fawcett, and Adam J. Davenport

Subjects
Cyclopentadiene, Stereochemistry, Organic Chemistry, Enantioselective synthesis, Absolute configuration, chemistry.chemical_element, Methacrolein, Oxazoline, Biochemistry, Medicinal chemistry, Catalysis, Rhodium, Inorganic Chemistry, chemistry.chemical_compound, chemistry, Materials Chemistry, Physical and Theoretical Chemistry, Diels–Alder reaction
Abstract

Reaction of [RhCl2Cp*]2 (Cp* = η-C5Me5) with salicyloxazolines in the presence of NaOMe gives complexes [RhCl(R-saloxaz)Cp*] (1–4) which have been fully characterised. The diastereoselectivity of complexation depends on the substituents and the absolute configuration at the metal centre is unstable in solution. Treatment of 2 with 4-methylpyridine and NaSbF6 in methanol at reflux gave [Rh(4-Mepy){(S)-iPr-saloxaz}Cp*][SbF6] (5) whilst [Rh(OH2)(Me2-saloxaz)Cp*][SbF6] (6) was prepared by reaction of 1 with AgSbF6. Three complexes, [RhCl(Me2-saloxaz)Cp*] (1), [RhCl{(S)-iPr-saloxaz}Cp*] (2), and [Rh(OH2)(Me2-saloxaz)Cp*][SbF6] (6) have been characterised by X-ray crystallography. Some of the complexes, after treatment with AgSbF6, have been tested as enantioselective catalysts for the Diels–Alder reaction of methacrolein with cyclopentadiene.

Published
2006

4. Arene–ruthenium complexes with salicyloxazolines: diastereoselective synthesis, configurational stability and applications as asymmetric catalysts for Diels–Alder reactions

Author

Adam J. Davenport, David L. Davies, David R. Russell, and John Fawcett

Subjects
Cyclopentadiene, Ligand, Stereochemistry, Enantioselective synthesis, Cationic polymerization, chemistry.chemical_element, Medicinal chemistry, Catalysis, Ruthenium, Inorganic Chemistry, chemistry.chemical_compound, chemistry, Benzene, Mesitylene
Abstract

Reaction of the dimers [RuCl2(η6-arene)]2 (arene = benzene, p-cymene, mesitylene) with salicyloxazolines in the presence of NaOMe gives complexes [RuCl(R-saloxaz)(arene)] (1–5) which have been fully characterised. Complexes [RuL(iPr-saloxaz)(mes)]Y (L = py, 2-Mepy, 4-Mepy; PPh3; Y− = SbF6 or BPh4) 6–9 were prepared by treating the chloride 2a with ligand L and NaY (Y− = SbF6 or BPh4) in methanol at reflux. Halide complexes [RuX(iPr-saloxaz)(mes)] (X = Br, 10; X = I, 11) were synthesised by treating 2a with AgSbF6 then with 1.2 equivalents of KBr or NaI, the methyl complex [RuMe(iPr-saloxaz)(mes)] 12 was synthesised from 2a by reaction with MeLi. Five complexes, [RuCl(iPr-saloxaz)(mes)] 2a, [RuCl(tBu-saloxaz)(p-cymene)] 3b, [RuCl(Ph-saloxaz)(mes)] 5a, [Ru(4-Mepy)(iPr-saloxaz)(mes)][SbF6] 7, and [Ru(PPh3)(iPr-saloxaz)(mes)][SbF6] 9, have been characterised by X-ray crystallography. Treatment of complexes 1–5 with AgSbF6 gives cationic species which are enantioselective catalysts for the Diels–Alder reaction of acroleins with cyclopentadiene, the effect of substituents on enantioselectivity has been examined.

Published
2004

5. Synthesis and structure of [2-{4(S)-isopropyl-2-oxazolinyl}phenyl]trimethyl tin and its reactivity as a carbometallating agent

Author

David L. Davies, David R. Russell, John Fawcett, and Adam J. Davenport

Subjects
Stereochemistry, Aryl, chemistry.chemical_element, General Chemistry, Crystal structure, Metathesis, Medicinal chemistry, Coupling reaction, chemistry.chemical_compound, chemistry, Lithium chloride, Reactivity (chemistry), Isopropyl, Palladium
Abstract

Reaction of LiL 3c (LH = 4(S)-isopropyl-2-oxazolinylbenzene) with Me3SnCl affords LSnMe33d. Attempts to transfer the oxazolinylphenyl to [RuCl2(mes)]2 or [RhCl2Cp*]2 using 3d failed, in both cases there is evidence for transfer of methyl with the formation of LSnMe2Cl 5. Reaction of 3d with [PdCl2(PhCN)2] leads to selective transfer of the aryloxazoline, forming [LPdCl]26 which has been prepared independently via metathesis of [LPd(OAc)]27 with lithium chloride. However, the reaction of 3d with [PdCl2(COD)] is not selective, transfer of both methyl and aryl occurring. The structures of 3d, 5 and 7 have been determined by X-ray diffraction.

Published
2002

6. Chiral pyridylimidazolines: synthesis, arene ruthenium complexes and application in asymmetric catalysis

Author

David R. Russell, John Fawcett, David L. Davies, and Adam J. Davenport

Subjects
chemistry.chemical_compound, Deprotonation, Cyclopentadiene, chemistry, Stereochemistry, Enantioselective synthesis, chemistry.chemical_element, Methacrolein, Lewis acids and bases, Medicinal chemistry, Ruthenium, Methyl iodide, Catalysis
Abstract

Condensation of (1S,2S)-1,2-diphenylethylenediamine and 2-cyanopyridine gives the chiral pyridylimidazoline (L1), deprotonation followed by treatment with methyl iodide gives an NMe derivative (L2). The pyridylimidazolines react with [RuCl2(mes)]2 (mes = 1,3,5-trimethylbenzene) in the presence of NaSbF6 to give [RuCl(L)(mes)][SbF6] (1,2) which have been characterised by X-ray crystallography. After treatment with AgSbF6 both complexes are enantioselective catalysts for the Diels–Alder reaction of methacrolein and cyclopentadiene.

Published
2001

7. Arene ruthenium complexes with pyridyloxazolines: synthesis and applications as asymmetric catalysts for Diels–Alder reactions †

Author

David R. Russell, Shaun A. Garratt, John Fawcett, David L. Davies, and Adam J. Davenport

Subjects
Stereochemistry, Enantioselective synthesis, Diastereomer, chemistry.chemical_element, General Chemistry, Crystal structure, Oxazoline, Medicinal chemistry, Catalysis, Ruthenium, chemistry.chemical_compound, chemistry, Diels alder, Lewis acids and bases
Abstract

Reaction of the dimers [RuCl2(arene)]2 with pyridyloxazolines (pymox) gave complexes [RuCl(pymox)(arene)][SbF6] 1–12 which have been fully characterised. Using chiral ligands diastereomers are formed, the diastereoselectivity depending on the substituents on the arene and on the oxazoline. The complexes [RuCl(Me2-pymox)(mes)][SbF6] 1, [RuCl(Ph-pymox)(mes)][SbF6] 3, [RuCl(iPr-pymox)(mes)][SbF6] 5 and [RuCl(indanyl-pymox)(mes)][SbF6] 12 (mes = mesitylene) have been characterised by X-ray crystallography. Treatment of these cations with AgSbF6 generates dications which in some cases can be isolated as aqua species [Ru(OH2)(pymox)(arene)]2+; these dications are enantioselective catalysts for Diels–Alder reactions of acroleins and dienes; a mechanism is proposed which accounts for the observed enantioselectivity.

Published
2000

9. Kinetic control of stereoselectivity of halide substitution in arene ruthenium pyridyloxazoline complexes; a rare case of net inversion†

Author

Adam J. Davenport, David L. Davies, Shaun A. Garratt, David R. Russell, and John Fawcett

Subjects
Chemistry, Ligand, Stereochemistry, Metals and Alloys, Diastereomer, Halide, chemistry.chemical_element, General Chemistry, Kinetic energy, Inversion (discrete mathematics), Catalysis, Surfaces, Coatings and Films, Electronic, Optical and Magnetic Materials, Ruthenium, Metal, Crystallography, visual_art, Materials Chemistry, Ceramics and Composites, visual_art.visual_art_medium, Stereoselectivity
Abstract

Reaction of [RuCl(Pri-pymox)(η6-mes)]+ 1b [Pri-pymox = 4-isopropyl-2-(2-pyridyl)-1,3-oxazoline, mes = 1,3,5-trimethylbenzene] with AgSbF6 then with halide gives [RuX(Pri-pymox)(η6-mes)]+ (X = Cl 1, Br 2, I 3), each as a mixture of diastereomers, the kinetic product being formed preferentially with net inversion of configuration at the metal; the structures of 2a and 2b have been determined by X-ray crystallography.

Published
1999

10. Synthesis of chiral half-sandwich rhodium oxazoline complexes and their use as asymmetric Diels–Alder catalysts

Author

David R. Russell, Latesh Lad, John Fawcett, and Adam J. Davenport

Subjects
Denticity, Cyclopentadiene, Chemistry, Metals and Alloys, Enantioselective synthesis, chemistry.chemical_element, Methacrolein, General Chemistry, Oxazoline, Catalysis, Surfaces, Coatings and Films, Electronic, Optical and Magnetic Materials, Rhodium, chemistry.chemical_compound, Polymer chemistry, Materials Chemistry, Ceramics and Composites, Diels alder, Organic chemistry
Abstract

The reaction of [(η-C5Me5)RhCl2]2 with bidentate oxazoline containing ligands provides the cations [(η-C5Me5)RhClL]+ 1–3, of which {1, L = 2,2′-isopropylidenebis[4-isopropyl-2-oxazoline] and 3, L = 4-isopropyl-2-(2-pyridyl)-1,3-oxazoline} are structurally characterised by X-ray diffraction; treatment of these with AgSbF6 gives dications which are enantioselective catalysts for the asymmetric Diels–Alder reaction between methacrolein and cyclopentadiene.

Published
1997

11. Using Electrophysiology and In SilicoThree-Dimensional Modeling to Reduce Human Ether-à-go-goRelated Gene K+Channel Inhibition in a Histamine H3 Receptor Antagonist Program.

Author

Adam J. Davenport, Clemens Möller, Alexander Heifetz, Michael P. Mazanetz, Richard J. Law, Andreas Ebneth, and Mark J. Gemkow

Subjects
ELECTROPHYSIOLOGY, ETHERS, POTASSIUM channels, SILICON, ATTENTION-deficit hyperactivity disorder, NEUROTRANSMITTERS, HISTAMINE, CENTRAL nervous system
Abstract

AbstractThe histamine H3 receptor (H3R) plays a regulatory role in the presynaptic release of histamine and several other neurotransmitters, and thus, it is an attractive target for central nervous system indications including cognitive disorders, narcolepsy, attention-deficit hyperactivity disorder, and pain. The development of H3R antagonists was complicated by the similarities between the pharmacophores of H3R and humanEther-à-go-go related gene (hERG) channel blockers, a fact that probably prevented promising compounds from being progressed into the clinic. Using a three-dimensionalin silico modeling approach complemented with automated and manual patch clamping, we were able to separate these two pharmacophores and to develop highly potent H3R antagonists with reduced risk of hERG liabilities from initial hit series with low selectivity identified in a high-throughput screening campaign. [ABSTRACT FROM AUTHOR]

Published
2010
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