Optimization of alpha-ketoamide based p38 inhibitors through modifications to the region that binds to the allosteric site.

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Montalban AG, Boman E, Chang CD, Ceide SC, Dahl R, Dalesandro D, Delaet NG, Erb E, Ernst JT, Gibbs A, Kahl J, Kessler L, Kucharski J, Lum C, Lundstrom J, Miller S, Nakanishi H, Roberts E, Saiah E, Sullivan R, Urban J, Wang Z, Larson CJ

Optimization of alpha-ketoamide based p38 inhibitors through modifications to the region that binds to the allosteric site.

Bioorg Med Chem Lett. 2010 Aug 15;20(16):4819-24. doi: 10.1016/j.bmcl.2010.06.102.

PubMed ID
20663667 [ View in PubMed
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Abstract

We have optimized a novel series of potent p38 MAP kinase inhibitors based on an alpha-ketoamide scaffold through structure based design that due to their extended molecular architecture bind, in addition to the ATP site, to an allosteric pocket. In vitro ADME, in vivo PK and efficacy studies show these compounds to have drug-like characteristics and have resulted in the nomination of a development candidate which is currently in phase II clinical trials for the oral treatment of inflammatory conditions.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
DoramapimodMitogen-activated protein kinase 14IC 50 (nM)44N/AN/ADetails
DoramapimodMitogen-activated protein kinase 14IC 50 (nM)17N/AN/ADetails