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Your search keyword '"Margaret J. Bradbury"' showing total 4 results
Start Over Author "Margaret J. Bradbury" Journal journal of medicinal chemistry
4 results on '"Margaret J. Bradbury"'

1. Characterization of novel selective H1-antihistamines for clinical evaluation in the treatment of insomnia

Author

Fabio C. Tucci, Lisa M. Hernández, Graham Beaton, Ajay Madan, Bin-Feng Li, Margaret J. Bradbury, Robert E. Petroski, Wilna J. Moree, Hua Wang, Dragan Marinkovic, Jinghua Yu, Jianyun Wen, Raymond S. Gross, Siobhan Malany, Florence Jovic, Paul D. Crowe, Said Zamani-Kord, Coon Timothy Richard, Zhihong O’Brien, Aida Sacaan, and Sam R. J. Hoare

Subjects
Tertiary amine, hERG, Pharmacology, Substrate Specificity, chemistry.chemical_compound, Pharmacokinetics, In vivo, Sleep Initiation and Maintenance Disorders, Drug Discovery, medicine, Animals, Dimethindene, Humans, Dosing, Sleep disorder, biology, Chemistry, Antagonist, Benzothiophene, Brain, Electroencephalography, medicine.disease, Receptors, Muscarinic, Ether-A-Go-Go Potassium Channels, Rats, Biochemistry, biology.protein, Histamine H1 Antagonists, Molecular Medicine, Sleep
Abstract

Analogues of the known H(1)-antihistamine R-dimethindene were profiled as potential agents for the treatment of insomnia. Several highly selective compounds were efficacious in rodent sleep models. On the basis of overall profile, indene 1d and benzothiophene 2a had pharmacokinetic properties suitable for evaluation in night time dosing. Compound 2a did not show an in vivo cardiovascular effect from weak hERG channel inhibition.

Published
2009

2. Characterization of thien-2-yl 1S,2R-milnacipran analogues as potent norepinephrine/serotonin transporter inhibitors for the treatment of neuropathic pain

Author

Mingzhu Zhang, Florence Jovic, Michael Johns, Troy Vickers, Joe A. Tran, Bin-Feng Li, Julie O'Brien, Margaret J. Bradbury, Jenny Wen, Rebecca R. Pick, John Saunders, Beth A. Fleck, Brian Dyck, Junko Tamiya, Alan C. Foster, Ajay Madan, Chen Chen, and Jonathan Grey

Subjects
Cyclopropanes, Male, Models, Molecular, Analgesic, Administration, Oral, Biological Availability, Pharmacology, Crystallography, X-Ray, Rats, Sprague-Dawley, chemistry.chemical_compound, Structure-Activity Relationship, Milnacipran, Drug Discovery, medicine, Animals, Humans, Neurotransmitter, Serotonin transporter, Pain Measurement, Serotonin Plasma Membrane Transport Proteins, Norepinephrine Plasma Membrane Transport Proteins, biology, Dose-Response Relationship, Drug, Molecular Structure, Stereoisomerism, Rats, Molecular Weight, Disease Models, Animal, Spinal Nerves, Biochemistry, chemistry, Drug Design, Neuropathic pain, Lipophilicity, biology.protein, Microsomes, Liver, Molecular Medicine, Neuralgia, Serotonin, Caco-2 Cells, Reuptake inhibitor, Selective Serotonin Reuptake Inhibitors, medicine.drug
Abstract

Thien-2-yl 1S,2R-milnacipran analogues were synthesized and characterized as norepinephrine/serotonin transporter inhibitors. These compounds possessed higher potencies than 1S,2R-milnacipran (2R-1) while maintaining low molecular weight and moderate lipophilicity, which are the important features for the pharmacological and pharmacokinetic characteristics of milnacipran (1). Thus, compound 5c exhibited IC50 values of 2.3 and 32 nM, respectively, at NET and SERT, which were more than 10-fold better than those of 1 (NET IC50 = 77 nM, SERT IC50 = 420 nM). Moreover, 5c achieved the same efficacy as 1, but with much lower doses, in a rodent spinal nerve ligation pain model. In addition, 5c displayed desirable pharmacokinetic properties in several species, including high oral availability and significant brain penetration.

Published
2008

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