Design and synthesis of potent, orally bioavailable dihydroquinazolinone inhibitors of p38 MAP kinase

The development of potent, orally bioavailable (in rat) and selective dihydroquinazolinone inhibitors of p38α MAP kinase is described. These analogues are hybrids of a pyridinylimidazole p38α inhibitor reported by Merck Research Laboratories and VX-745. Optimization of the C-5 phenyl and the C-7 pip...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2003-01, Vol.13 (2), p.277-280
Hauptverfasser:	Stelmach, John E., Liu, Luping, Patel, Sangita B., Pivnichny, James V., Scapin, Giovanna, Singh, Suresh, Hop, Cornelis E.C.A., Wang, Zhen, Strauss, John R., Cameron, Patricia M., Nichols, Elizabeth A., O'Keefe, Stephen J., O'Neill, Edward A., Schmatz, Dennis M., Schwartz, Cheryl D., Thompson, Chris M., Zaller, Dennis M., Doherty, James B.
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Area Under Curve Biological and medical sciences Biological Availability Drug Design Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - pharmacokinetics Enzyme Inhibitors - pharmacology In Vitro Techniques Medical sciences Microsomes, Liver - drug effects Microsomes, Liver - metabolism Miscellaneous Mitogen-Activated Protein Kinases - antagonists & inhibitors Models, Molecular Molecular Conformation Monocytes - drug effects Monocytes - metabolism p38 Mitogen-Activated Protein Kinases Pharmacology. Drug treatments Quinazolines - chemical synthesis Quinazolines - pharmacology Rats Structure-Activity Relationship Tumor Necrosis Factor-alpha - antagonists & inhibitors Tumor Necrosis Factor-alpha - biosynthesis
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Zusammenfassung:	The development of potent, orally bioavailable (in rat) and selective dihydroquinazolinone inhibitors of p38α MAP kinase is described. These analogues are hybrids of a pyridinylimidazole p38α inhibitor reported by Merck Research Laboratories and VX-745. Optimization of the C-5 phenyl and the C-7 piperidinyl substituents led to the identification of 15i which gave excellent suppression of TNF-α production in LPS-stimulated whole blood (IC 50=10 nM) and good oral exposure in rats (F=68%, AUCn PO=0.58 μM h). Graphic
ISSN:	0960-894X 1464-3405
DOI:	10.1016/S0960-894X(02)00752-7