Substituted N-aryl-6-pyrimidinones: a new class of potent, selective, and orally active p38 MAP kinase inhibitors.

Article Details

Citation

Devadas B, Selness SR, Xing L, Madsen HM, Marrufo LD, Shieh H, Messing DM, Yang JZ, Morgan HM, Anderson GD, Webb EG, Zhang J, Devraj RV, Monahan JB

Substituted N-aryl-6-pyrimidinones: a new class of potent, selective, and orally active p38 MAP kinase inhibitors.

Bioorg Med Chem Lett. 2011 Jul 1;21(13):3856-60. doi: 10.1016/j.bmcl.2011.05.006. Epub 2011 May 8.

PubMed ID
21620699 [ View in PubMed
]
Abstract

A novel series of highly potent and selective p38 MAP kinase inhibitors was developed originating from a substituted N-aryl-6-pyrimidinone scaffold. SAR studies coupled with in vivo evaluations in rat arthritis model culminated in the identification of 10 with excellent oral efficacy. Compound 10 exhibited a significantly enhanced dissolution rate compared to 1, translating to a high oral bioavailability (>90%) in rat. In animal studies 10 inhibited LPS-stimulated production of tumor necrosis factor-alpha in a dose-dependent manner and demonstrated robust efficacy comparable to dexamethasone in a rat streptococcal cell wall-induced arthritis model.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
PH-797804Mitogen-activated protein kinase 14IC 50 (nM)1.05N/AN/ADetails
PH-797804Mitogen-activated protein kinase 14IC 50 (nM)17.4N/AN/ADetails
PH-797804Mitogen-activated protein kinase 14Ki (nM)2.9N/AN/ADetails