10201-71-5Relevant articles and documents
Utilization of a Hydrogen Source from Renewable Lignocellulosic Biomass for Hydrogenation of Nitroarenes
Tan, Fang-Fang,Tang, Kai-Li,Zhang, Ping,Guo, Yan-Jun,Qu, Mengnan,Li, Yang
, p. 4189 - 4195 (2019)
Exploring of hydrogen source from renewable biomass, such as glucose in alkaline solution, for hydrogenation reactions had been studied since 1860s. According to proposed pathway, only small part of hydrogen source in glucose was utilized. Herein, the utilization of a hydrogen source from renewable lignocellulosic biomass, one of the most abundant renewable sources in nature, for a hydrogenation reaction is described. The hydrogenation is demonstrated by reduction of nitroarenes to arylamines in up to 95 % yields. Mechanism studies suggest that the hydrogenation occurs via a hydrogen transformation pathway.
Stepwise Design of γ-Secretase Modulators with an Advanced Profile by Judicious Coordinated Structural Replacements and an Unconventional Phenyl Ring Bioisostere
Rodríguez Sarmiento, Rosa María,Bissantz, Caterina,Bylund, Johan,Limberg, Anja,Neidhart, Werner,Jakob-Roetne, Roland,Wang, Lisha,Baumann, Karlheinz
, p. 8534 - 8553 (2020)
Starting from RO6800020 (1), our former γ-secretase modulator (GSM) lead compound, we utilized sequential structural replacements to improve the potency (IC50), pharmacokinetic properties including the free fraction (fraction unbound (fu)) in plasma, and in vivo efficacy. Importantly, we used novel CF3-alkoxy groups as bioisosteric replacements of a fluorinated phenyl ring and properties such as lipophilicity, solubility, metabolic stability, and free fraction could be balanced, maintaining low Pgp efflux needed for CNS penetration. In addition, by reducing aromaticity, we prevented phototoxicity. Additional substitution in the triazolopyridine core disturbed the binding to phosphatidylinositol 4-kinase, catalytic β (PIK4CB). We also introduced less lipophilic head heterocycles devoid of covalent binding (CVB) liability. After these changes, further modifications to the trifluoroethoxy bioisosteric replacement allowed rebalancing of properties, such as lipophilicity, and also potency. Our optimization strategy culminated with in vivo active RO7101556 (18B) having excellent properties and being selected as an advanced candidate.
Discovery and Early Clinical Development of Isobutyl 1-[8-Methoxy-5-(1-oxo-3 H-isobenzofuran-5-yl)-[1,2,4]triazolo[1,5- a]pyridin-2-yl]cyclopropanecarboxylate (LEO 39652), a Novel "dual-Soft" PDE4 Inhibitor for Topical Treatment of Atopic Dermatitis
Larsen, Jens,Lambert, Maja,Pettersson, Henrik,Vifian, Thomas,Larsen, Mogens,Ollerstam, Anna,Hegardt, Pontus,Eskilsson, Cecilia,Laursen, Steen,Soehoel, Anders,Skak-Nielsen, Tine,Hansen, Lene M.,Knudsen, Nina ?.,Eirefelt, Stefan,S?rensen, Morten D.,Stilou, Tatiana G.,Nielsen, Simon F.
, p. 14502 - 14521 (2020/11/19)
We describe the design of a novel PDE4 scaffold and the exploration of the dual-soft concept to reduce systemic side effects via rapid elimination: introducing ester functionalities that can be inactivated in blood as well as by the liver (dual-soft) while being stable in human skin. Compound 40 was selected as a clinical candidate as it was potent and rapidly degraded by blood and liver to inactive metabolites and because in preclinical studies it showed high exposure at the target organ: the skin. Preclinical and clinical data are presented confirming the value of the dual-soft concept in reducing systemic exposure.
