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Abstract: A novel class of pyrazolopyridazine p38α mitogen-activated protein kinase (MAPK) inhibitors is disclosed. A structure activity relationship (SAR) investigation was conducted driven by the ability of these compounds to inhibit the p38α enzyme, the secretion of TNFα in a LPS-challenged THP1 cell line and TNFα-induced production of IL-8 in the presence of 50% human whole blood (hWB). This study resulted in the discovery of several inhibitors with IC50 values in the single-digit nanomolar range in hWB. Further investigation of the pharmacokinetic profiles of these lead compounds led to the identification of three potent and orally bioavailable p38α inhibitors 2h, 2m, and 13h. Inhibitor 2m was found to be highly selective for p38α/β over a panel of 402 other kinases in Ambit screening, and was highly efficacious in vivo in the inhibition of TNFα production in LPS-stimulated Lewis rats with an ED50 of ca. 0.08mg/kg. [Copyright &y& Elsevier]

Abstract: A novel class of fused pyrazole-derived inhibitors of p38α mitogen-activated protein kinase (MAPK) is disclosed. These inhibitors were evaluated for their ability to inhibit the p38α enzyme, the secretion of TNFα in a LPS-challenged THP1 cell line and TNFα-induced production of IL-8 in 50% human whole blood. This series was optimized through a SAR investigation to provide inhibitors with IC50 values in the low single-digit nanomolar range in whole blood. Further investigation of their pharmacokinetic profiles led to the identification of two potent and orally bioavailable p38 inhibitors 10m and 10q. Inhibitor 10m was found to be efficacious in vivo in the inhibition of TNFα production in LPS-stimulated Lewis rats with an ED50 of 0.1mg/kg while 10q was found to have an ED50 of 0.05–0.07mg/kg. [Copyright &y& Elsevier]

Replacement of the piperazine sulfonamide portion of the PI3Kα inhibitor AMG 511 ( 1 ) with a range of aliphatic alcohols led to the identification of a truncated gem -dimethylbenzylic alcohol analog, 2-(5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-((5-fluoro-6-methoxypyridin-3-yl)amino)pyridin-3-yl)propan-2-ol ( 7 ). This compound possessed good in vitro efficacy and pharmacokinetic parameters and demonstrated an EC 50 of 239 ng/mL in a mouse liver pharmacodynamic model measuring the inhibition of hepatocyte growth factor (HGF)-induced Akt Ser473 phosphorylation in CD1 nude mice 6 h post-oral dosing. [ABSTRACT FROM AUTHOR]

The phosphoinositide 3-kinase family catalyzes the phosphorylationof phosphatidylinositol-4,5-diphosphate to phosphatidylinositol-3,4,5-triphosphate,a secondary messenger which plays a critical role in important cellularfunctions such as metabolism, cell growth, and cell survival. Ourefforts to identify potent, efficacious, and orally available phosphatidylinositol3-kinase (PI3K) inhibitors as potential cancer therapeutics have resultedin the discovery of 4-(2-((6-methoxypyridin-3-yl)amino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine(1). In this paper, we describe the optimization of compound 1, which led to the design and synthesis of pyridyltriazine 31, a potent pan inhibitor of class I PI3Ks with a superiorpharmacokinetic profile. Compound 31was shown to potentlyblock the targeted PI3K pathway in a mouse liver pharmacodynamic modeland inhibit tumor growth in a U87 malignant glioma glioblastoma xenograftmodel. On the basis of its excellent in vivo efficacy and pharmacokineticprofile, compound 31was selected for further evaluationas a clinical candidate and was designated AMG 511. [ABSTRACT FROM AUTHOR]

Abstract: Phosphoinositide 3-kinase (PI3K) is an important target in oncology due to the deregulation of the PI3K/Akt signaling pathway in a wide variety of tumors. A series of 4-amino-6-methyl-1,3,5-triazine sulfonamides were synthesized and evaluated as inhibitors of PI3K. The synthesis, in vitro biological activities, pharmacokinetic and in vivo pharmacodynamic profiling of these compounds are described. The most promising compound from this investigation (compound 3j) was found to be a pan class I PI3K inhibitor with a moderate (>10-fold) selectivity over the mammalian target of rapamycin (mTOR) in the enzyme assay. In a U87 MG cellular assay measuring phosphorylation of Akt, compound 3j displayed low double digit nanomolar IC50 and exhibited good oral bioavailability in rats (F oral =63%). Compound 3j also showed a dose dependent reduction in the phosphorylation of Akt in a U87 tumor pharmacodynamic model with a plasma EC50 =193nM (91ng/mL). [Copyright &y& Elsevier]

Abstract: Structure–activity relationship (SAR) investigations of a novel class of triazolopyridazinone p38α mitogen activated protein kinase (MAPK) inhibitors are disclosed. From these studies, increased in vitro potency was observed for 2,6-disubstituted phenyl moieties and N-ethyl triazolopyridazinone cores due to key contacts with Leu108, Ala157 and Val38. Further investigation led to the identification of three compounds, 3g, 3j and 3m that are highly potent inhibitors of LPS-induced MAPKAP kinase 2 (MK2) phosphorylation in 50% human whole blood (hWB), and possess desirable in vivo pharmacokinetic and kinase selectivity profiles. [Copyright &y& Elsevier]