Search

Your search keyword '"Smee PA"' showing total 3 results
Start Over Author "Smee PA" Publisher elsevier science ltd
3 results on '"Smee PA"'

1. Biphenyl amide p38 kinase inhibitors 3: Improvement of cellular and in vivo activity.

Author

Angell R, Aston NM, Bamborough P, Buckton JB, Cockerill S, deBoeck SJ, Edwards CD, Holmes DS, Jones KL, Laine DI, Patel S, Smee PA, Smith KJ, Somers DO, and Walker AL

Subjects
Administration, Oral, Animals, Benzamides blood, Benzamides chemistry, Biphenyl Compounds blood, Biphenyl Compounds chemistry, Combinatorial Chemistry Techniques, Crystallography, X-Ray, Disease Models, Animal, Molecular Conformation, Molecular Structure, Protein Kinase Inhibitors blood, Protein Kinase Inhibitors chemistry, Rats, Benzamides chemical synthesis, Benzamides pharmacology, Biphenyl Compounds chemical synthesis, Biphenyl Compounds pharmacology, Mitogen-Activated Protein Kinase 14 antagonists & inhibitors, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacology
Abstract

The biphenyl amides (BPAs) are a novel series of p38alpha MAP kinase inhibitor. The optimisation of the series to give compounds that are potent in an in vivo disease model is discussed. SAR is presented and rationalised with reference to the crystallographic binding mode.

Published
2008
Full Text
View/download PDF

2. Biphenyl amide p38 kinase inhibitors 4: DFG-in and DFG-out binding modes.

Author

Angell RM, Angell TD, Bamborough P, Bamford MJ, Chung CW, Cockerill SG, Flack SS, Jones KL, Laine DI, Longstaff T, Ludbrook S, Pearson R, Smith KJ, Smee PA, Somers DO, and Walker AL

Subjects
Amides blood, Amides chemistry, Amino Acids genetics, Amino Acids metabolism, Binding Sites, Biphenyl Compounds blood, Biphenyl Compounds chemistry, Combinatorial Chemistry Techniques, Crystallography, X-Ray, Drug Design, Lipopolysaccharides pharmacology, Molecular Conformation, Molecular Structure, Naphthalenes pharmacology, Pyrazoles pharmacology, Structure-Activity Relationship, Amides chemical synthesis, Amides pharmacology, Biphenyl Compounds chemical synthesis, Biphenyl Compounds pharmacology, Mitogen-Activated Protein Kinase 14 antagonists & inhibitors
Abstract

The biphenyl amides (BPAs) are a series of p38alpha MAP kinase inhibitors. Compounds are able to bind to the kinase in either the DFG-in or DFG-out conformation, depending on substituents. X-ray, binding, kinetic and cellular data are shown, providing the most detailed comparison to date between potent compounds from the same chemical series that bind to different p38alpha conformations. DFG-out-binding compounds could be made more potent than DFG-in-binding compounds by increasing their size. Unexpectedly, compounds that bound to the DGF-out conformation showed diminished selectivity. The kinetics of binding to the isolated enzyme and the effects of compounds on cells were largely unaffected by the kinase conformation bound.

Published
2008
Full Text
View/download PDF

3. Biphenyl amide p38 kinase inhibitors 2: Optimisation and SAR.

Author

Angell RM, Angell TD, Bamborough P, Brown D, Brown M, Buckton JB, Cockerill SG, Edwards CD, Jones KL, Longstaff T, Smee PA, Smith KJ, Somers DO, Walker AL, and Willson M

Subjects
Administration, Oral, Amides chemistry, Amides pharmacokinetics, Animals, Arthritis, Experimental drug therapy, Arthritis, Experimental metabolism, Biphenyl Compounds chemistry, Biphenyl Compounds pharmacokinetics, Crystallography, X-Ray, Models, Molecular, Molecular Conformation, Oxadiazoles chemistry, Oxadiazoles pharmacokinetics, Oxadiazoles pharmacology, Piperazines chemistry, Piperazines pharmacokinetics, Piperazines pharmacology, Protein Binding, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacokinetics, Rats, Structure-Activity Relationship, p38 Mitogen-Activated Protein Kinases chemistry, p38 Mitogen-Activated Protein Kinases metabolism, Amides pharmacology, Biphenyl Compounds pharmacology, Protein Kinase Inhibitors pharmacology, p38 Mitogen-Activated Protein Kinases antagonists & inhibitors
Abstract

The biphenyl amides are a novel series of p38 MAP kinase inhibitors. Structure-activity relationships of the series against p38alpha are discussed with reference to the X-ray crystal structure of an example. The series was optimised rapidly to a compound showing oral activity in an in vivo disease model.

Published
2008
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results