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4 results on '"Natarajan SR"'

1. Synthesis and biological activity of pyridopyridazin-6-one p38α MAP kinase inhibitors. Part 2.

Author

Tynebor RM, Chen MH, Natarajan SR, O'Neill EA, Thompson JE, Fitzgerald CE, O'Keefe SJ, and Doherty JB

Subjects
Animals, Dogs, Dose-Response Relationship, Drug, Haplorhini, Humans, Mitogen-Activated Protein Kinase 14 metabolism, Molecular Structure, Protein Kinase Inhibitors administration & dosage, Pyridazines administration & dosage, Pyridines administration & dosage, Rats, Structure-Activity Relationship, Mitogen-Activated Protein Kinase 14 antagonists & inhibitors, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacology, Pyridazines chemical synthesis, Pyridazines pharmacology, Pyridines chemical synthesis, Pyridines pharmacology
Abstract

This manuscript concludes the Structure Activity Relationship (SAR) on the pyridazinone scaffold and identifies a compound with subnanomolar p38α activity and 24h coverage in the rat arthritis efficacy model., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Published
2012
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2. Synthesis and biological activity of pyridopyridazin-6-one p38 MAP kinase inhibitors. Part 1.

Author

Tynebor RM, Chen MH, Natarajan SR, O'Neill EA, Thompson JE, Fitzgerald CE, O'Keefe SJ, and Doherty JB

Subjects
Animals, Binding Sites, Catalytic Domain, Computer Simulation, Mitogen-Activated Protein Kinase 14 metabolism, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacokinetics, Protein Structure, Tertiary, Pyridazines chemical synthesis, Pyridazines pharmacokinetics, Rats, Structure-Activity Relationship, Mitogen-Activated Protein Kinase 14 antagonists & inhibitors, Protein Kinase Inhibitors chemical synthesis, Pyridazines chemistry
Abstract

The development and synthesis of potent p38α MAP kinase inhibitors containing a pyridazinone platform is described. Evolution of the p38α selective pyridopyridazin-6-one series from the p38α/β dual inhibitor 2H-quinolizin-2-one series will be discussed in full detail., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Published
2011
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3. p38 MAP kinase inhibitors. Part 6: 2-arylpyridazin-3-ones as templates for inhibitor design.

Author

Natarajan SR, Heller ST, Nam K, Singh SB, Scapin G, Patel S, Thompson JE, Fitzgerald CE, and O'Keefe SJ

Subjects
Binding Sites, Drug Design, Glycine chemistry, Structure-Activity Relationship, Tyrosine chemistry, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, Pyridazines chemical synthesis, Pyridazines pharmacology, p38 Mitogen-Activated Protein Kinases antagonists & inhibitors
Abstract

p38 inhibitors based on 3,4-dihydropyrido[4,3-d]pyrimidazin-2-one template were synthesized and their SAR explored. Benchmark compounds 30, 35, and 36 were found to be potent against the enzyme. Crystal structure of p38 in complex with 30 indicated a key pi-stacking interaction with the pendant tyrosine residue-35 in the glycine-rich loop.

Published
2006
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4. p38 MAP kinase inhibitors. Part 3: SAR on 3,4-dihydropyrimido[4,5-d]pyrimidin-2-ones and 3,4-dihydropyrido[4,3-d]pyrimidin-2-ones.

Author

Natarajan SR, Wisnoski DD, Thompson JE, O'Neill EA, and O'Keefe SJ

Subjects
Chemistry, Pharmaceutical methods, Drug Design, Enzyme Inhibitors metabolism, Enzyme Inhibitors pharmacology, Humans, Inhibitory Concentration 50, Models, Chemical, Pyridazines pharmacology, Pyridines chemistry, Pyrimidines pharmacology, Pyrimidinones pharmacology, Quinazolines chemistry, Structure-Activity Relationship, p38 Mitogen-Activated Protein Kinases chemistry, Enzyme Inhibitors chemistry, Pyridazines chemistry, Pyrimidines chemistry, Pyrimidinones chemistry, p38 Mitogen-Activated Protein Kinases antagonists & inhibitors
Abstract

p38 inhibitors based on 3,4-dihydropyrimido[4,5-d]pyrimidin-2-one and 3,4-dihydropyrido[4,3-d]pyrimidin-2-one platforms were synthesized and preliminary SAR explored. Among the pyrimido-pyrimidones the emergence of two sub-types of analogs-C7-amino-pyrimidines such as 24 and C7-amino-piperidines such as 42-characterized with good p38 inhibition and better off-target profiles in terms of ion channel activities was significant. Representative compound 54 in the pyrido-pyrimidone class was found to be equipotent with corresponding analog in the quinazolinone series.

Published
2006
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