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

Article Details

Citation

Stelmach JE, Liu L, Patel SB, Pivnichny JV, Scapin G, Singh S, Hop CE, Wang Z, Strauss JR, Cameron PM, Nichols EA, O'Keefe SJ, O'Neill EA, Schmatz DM, Schwartz CD, Thompson CM, Zaller DM, Doherty JB

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

Bioorg Med Chem Lett. 2003 Jan 20;13(2):277-80.

PubMed ID
12482439 [ View in PubMed
]
Abstract

The development of potent, orally bioavailable (in rat) and selective dihydroquinazolinone inhibitors of p38alpha MAP kinase is described. These analogues are hybrids of a pyridinylimidazole p38alpha 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-alpha production in LPS-stimulated whole blood (IC(50)=10nM) and good oral exposure in rats (F=68%, AUCn PO=0.58 microM h).

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Mitogen-activated protein kinase 14Q16539Details
Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
1-(2,6-Dichlorophenyl)-5-(2,4-Difluorophenyl)-7-Piperazin-1-Yl-3,4-Dihydroquinazolin-2(1h)-OneMitogen-activated protein kinase 14IC 50 (nM)2.6N/AN/ADetails