6257-49-4Relevant articles and documents
Design, Synthesis, and Pharmacological Characterization of a Neutral, Non-Prodrug Thrombin Inhibitor with Good Oral Pharmacokinetics
Hillisch, Alexander,Gericke, Kersten M.,Allerheiligen, Swen,Roehrig, Susanne,Schaefer, Martina,Tersteegen, Adrian,Schulz, Simone,Lienau, Philip,Gnoth, Mark,Puetter, Vera,Hillig, Roman C.,Heitmeier, Stefan
supporting information, p. 12574 - 12594 (2020/11/13)
Despite extensive research on small molecule thrombin inhibitors for oral application in the past decades, only a single double prodrug with very modest oral bioavailability has reached human therapy as a marketed drug. We have undertaken major efforts to identify neutral, non-prodrug inhibitors. Using a holistic analysis of all available internal data, we were able to build computational models and apply these for the selection of a lead series with the highest possibility of achieving oral bioavailability. In our design, we relied on protein structure knowledge to address potency and identified a small window of favorable physicochemical properties to balance absorption and metabolic stability. Protein structure information on the pregnane X receptor helped in overcoming a persistent cytochrome P450 3A4 induction problem. The selected compound series was optimized to a highly potent, neutral, non-prodrug thrombin inhibitor by designing, synthesizing, and testing derivatives. The resulting optimized compound, BAY1217224, has reached first clinical trials, which have confirmed the desired pharmacokinetic properties.
Manganese catalyzed reductive amination of aldehydes using hydrogen as a reductant
Wei, Duo,Bruneau-Voisine, Antoine,Valyaev, Dmitry A.,Lugan, No?l,Sortais, Jean-Baptiste
supporting information, p. 4302 - 4305 (2018/05/03)
A one-pot two-step procedure was developed for the alkylation of amines via reductive amination of aldehydes using molecular dihydrogen as a reductant in the presence of a manganese pyridinyl-phosphine complex as a pre-catalyst. After the initial condensation step, the reduction of imines formed in situ is performed under mild conditions (50-100 °C) with 2 mol% of catalyst and 5 mol% of tBuOK under 50 bar of hydrogen. Excellent yields (>90%) were obtained for a large combination of aldehydes and amines (40 examples), including aliphatic aldehydes and amino-alcohols.
Structure-based design of potent and selective 3-phosphoinositide-dependent kinase-1 (PDK1) inhibitors
Medina, Jesús R.,Becker, Christopher J.,Blackledge, Charles W.,Duquenne, Celine,Feng, Yanhong,Grant, Seth W.,Heerding, Dirk,Li, William H.,Miller, William H.,Romeril, Stuart P.,Scherzer, Daryl,Shu, Arthur,Bobko, Mark A.,Chadderton, Antony R.,Dumble, Melissa,Gardiner, Christine M.,Gilbert, Seth,Liu, Qi,Rabindran, Sridhar K.,Sudakin, Valery,Xiang, Hong,Brady, Pat G.,Campobasso, Nino,Ward, Paris,Axten, Jeffrey M.
experimental part, p. 1871 - 1895 (2011/05/30)
Phosphoinositide-dependent protein kinase-1(PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly deregulated across all cancers, a selective inhibitor of PDK1 might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1 toward highly potent and selective PDK1 inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OCl-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDK1 and the potential pharmacological uses of a PDK1 inhibitor.
