p38 MAP kinase inhibitors. Part 5: Discovery of an orally bio-available and highly efficacious compound based on the 7-amino-naphthyridone scaffold
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 mode...
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| Published in | Bioorganic & medicinal chemistry letters Vol. 16; no. 20; pp. 5468 - 5471 |
|---|---|
| Main Authors | , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Oxford
Elsevier Ltd
15.10.2006
Elsevier |
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| Abstract | 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. |
|---|---|
| AbstractList | 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 0.2mpk. 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. 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 sub(50) doses as low as 0.2 mpk. |
| Author | O’Keefe, Stephen J. Levorse, Mark Visco, Denise M. O’Neill, Edward A. Carballo-Jane, Ester Cvetovich, Raymond Chung, John Y. Natarajan, Swaminathan R. Liu, Luping Vora, Kalpit A. Thompson, James E. |
| Author_xml | – sequence: 1 givenname: Swaminathan R. surname: Natarajan fullname: Natarajan, Swaminathan R. email: ravi_natarajan@merck.com organization: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA – sequence: 2 givenname: Luping surname: Liu fullname: Liu, Luping organization: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA – sequence: 3 givenname: Mark surname: Levorse fullname: Levorse, Mark organization: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA – sequence: 4 givenname: James E. surname: Thompson fullname: Thompson, James E. organization: Department of Inflammation Research, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA – sequence: 5 givenname: Edward A. surname: O’Neill fullname: O’Neill, Edward A. organization: Department of Inflammation Research, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA – sequence: 6 givenname: Stephen J. surname: O’Keefe fullname: O’Keefe, Stephen J. organization: Department of Inflammation Research, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA – sequence: 7 givenname: Kalpit A. surname: Vora fullname: Vora, Kalpit A. organization: Department of Inflammation Research, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA – sequence: 8 givenname: Raymond surname: Cvetovich fullname: Cvetovich, Raymond organization: Department of Process Research, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA – sequence: 9 givenname: John Y. surname: Chung fullname: Chung, John Y. organization: Department of Process Research, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA – sequence: 10 givenname: Ester surname: Carballo-Jane fullname: Carballo-Jane, Ester organization: Department of AnimalPharmacolgy, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA – sequence: 11 givenname: Denise M. surname: Visco fullname: Visco, Denise M. organization: Department of LAR, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA |
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| Cites_doi | 10.1016/S0960-894X(02)00876-4 10.1021/jm030585i 10.1016/S0960-894X(02)00752-7 10.1016/S0960-894X(02)00990-3 10.1128/IAI.61.3.970-974.1993 |
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| Keywords | 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 |
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| References | Natarajan, S. R.; Wisnoski, D. D.; Thompson, J. E.; O’Neill, E. A.; O’Keefe, S. J.; Zaller, D. M.; Doherty, J. B. Ali, Thompson, Balkovec, Graham, Hammond, Quraishi, Tata, Einstein, Ge, Harris, Kelly, Mazur, Pandit, Santoro, Sitlani, Wang, Williamson, Miller, Thompson, Zaller, Forrest, Carballo-Jane, Luell, Gonzales, Johnson, Morrison, Freudenberg, Galanos, Silverstein (bib4) 2004; 47 Hunt, Kallashi, Ruzek, Sinclair, Ita, McCormick, Pivnichny, Hop, Kumar, Wang, O’Keefe, O’Neill, Porter, Thompson, Woods, Zaller, Doherty (bib3) 2003; 13 Bemis, G. W.; Salituro, F. G.; Duffy, J. P.; Harrington, E. M. U.S. Patent 2000, 6,147,080. 2, in press. 10.1016/j.bmcl.2006.06.084_bib1_3 Natarajan (10.1016/j.bmcl.2006.06.084_bib1_1) 2003; 13 Hunt (10.1016/j.bmcl.2006.06.084_bib3) 2003; 13 Ali (10.1016/j.bmcl.2006.06.084_bib4_1) 2004; 47 Stelmach (10.1016/j.bmcl.2006.06.084_bib1_2) 2003; 13 10.1016/j.bmcl.2006.06.084_bib2 Gonzales (10.1016/j.bmcl.2006.06.084_bib4_2) 1993; 61 |
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| Snippet | A new sub-class of p38 inhibitors represented by 7-amino-naphthyridone have been discovered. Benchmark compound
16 potently inhibited p38 in vitro, was... A new sub-class of p38 inhibitors represented by 7-amino-naphthyridone have been discovered. Benchmark compound 16 potently inhibited p38 in vitro, was... |
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| SubjectTerms | 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 |
| Title | p38 MAP kinase inhibitors. Part 5: Discovery of an orally bio-available and highly efficacious compound based on the 7-amino-naphthyridone scaffold |
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