p38 MAP kinase inhibitors. Part 5: Discovery of an orally bio-available and highly efficacious compound based on the 7-amino-naphthyridone scaffold

• Published in: Bioorganic & medicinal chemistry letters Vol. 16; no. 20; pp. 5468 - 5471
• Main Authors: Natarajan, Swaminathan R., Liu, Luping, Levorse, Mark, Thompson, James E., O’Neill, Edward A., O’Keefe, Stephen J., Vora, Kalpit A., Cvetovich, Raymond, Chung, John Y., Carballo-Jane, Ester, Visco, Denise M.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.10.2006; Elsevier
• Subjects: 7-Amino-naphthyridones; Administration, Oral; Animals; Binding Sites; Biological and medical sciences; Biological Availability; Bones, joints and connective tissue. Antiinflammatory agents; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Drug Evaluation, Preclinical; Enzyme Activation - drug effects; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacokinetics; Humans; In Vitro Techniques; Lipopolysaccharides - pharmacology; Macaca mulatta; Male; Medical sciences; Mice; Mice, Inbred BALB C; Microsomes, Liver - drug effects; Molecular Structure; Monocytes - drug effects; Naphthyridines - administration & dosage; Naphthyridines - chemistry; Naphthyridines - pharmacokinetics; p38 MAP kinase inhibitors; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; Peptide flip; Pharmacology. Drug treatments; Rat LPS challenge; Rats; Rats, Sprague-Dawley; Stereoisomerism; Structure-Activity Relationship; Tumor Necrosis Factor-alpha - antagonists & inhibitors; p38 MAP kinase inhibitors; Peptide flip; Rat LPS challenge; 7-Amino-naphthyridones; Peptides; Rat; Signal transduction; Naphtyridine derivatives; Chemical synthesis; Enzyme; Transferases; Rodentia; Antiinflammatory agent; Oral administration; Enzyme inhibitor; Mitogen-activated protein kinase; Inflammation; In vitro; Biological activity; In vivo; Vertebrata; Mammalia; Protein kinase; Animal; Models; Fluorine Organic compounds; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2006.06.084

A new sub-class of p38 inhibitors represented by 7-amino-naphthyridone have been discovered. Benchmark compound 16 potently inhibited p38 in vitro, was functionally active, and displayed excellent pharmacokinetic profiles in two animal species. Compound 16 reduced inflammation in animal disease models at EC 50 doses as low as 0.2 mpk.