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

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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
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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