239074-29-4Relevant articles and documents
Radical hydroxymethylation of alkyl iodides using formaldehyde as a C1 synthon
Caiger, Lewis,Constantin, Timothée,Douglas, James J.,Juliá, Fabio,Leonori, Daniele,Sheikh, Nadeem S.,Sinton, Conar
, p. 10448 - 10454 (2021/08/20)
Radical hydroxymethylation using formaldehyde as a C1 synthon is challenging due to the reversible and endothermic nature of the addition process. Here we report a strategy that couples alkyl iodide building blocks with formaldehyde through the use of photocatalysis and a phosphine additive. Halogen-atom transfer (XAT) from α-aminoalkyl radicals is leveraged to convert the iodide into the corresponding open-shell species, while its following addition to formaldehyde is rendered irreversible by trapping the transient O-radical with PPh3. This event delivers a phosphoranyl radical that re-generates the alkyl radical and provides the hydroxymethylated product.
Discovery of a Gut-Restricted JAK Inhibitor for the Treatment of Inflammatory Bowel Disease
Leonard, Kristi A.,Madge, Lisa A.,Krawczuk, Paul J.,Wang, Aihua,Kreutter, Kevin D.,Bacani, Genesis M.,Chai, Wenying,Smith, Russell C.,Tichenor, Mark S.,Harris, Michael C.,Malaviya, Ravi,Seierstad, Mark,Johnson, Marguerite E.,Venable, Jennifer D.,Kim, Suzie,Hirst, Gavin C.,Mathur, Ashok S.,Rao, Tadimeti S.,Edwards, James P.,Rizzolio, Michele C.,Koudriakova, Tatiana
, p. 2915 - 2929 (2020/04/08)
To identify Janus kinase (JAK) inhibitors that selectively target gastrointestinal tissues with limited systemic exposures, a class of imidazopyrrolopyridines with a range of physical properties was prepared and evaluated. We identified compounds with low intrinsic permeability and determined a correlation between permeability and physicochemical properties, clogP and tPSA, for a subset of compounds. This low intrinsic permeability translated into compounds displaying high colonic exposure and low systemic exposure after oral dosing at 25 mg/kg in mouse. In a mouse PK/PD model, oral dosing of lead compound 2 demonstrated dose-dependent inhibition of pSTAT phosphorylation in colonic explants post-oral dose but low systemic exposure and no measurable systemic pharmacodynamic activity. We thus demonstrate the utility of JAK inhibitors with low intrinsic permeability as a feasible approach to develop gut-restricted, pharmacologically active molecules with a potential advantage over systemically available compounds that are limited by systemic on-target adverse events.
D2 Dopamine Receptor G Protein-Biased Partial Agonists Based on Cariprazine
Shen, Yudao,McCorvy, John D.,Martini, Michael L.,Rodriguiz, Ramona M.,Pogorelov, Vladimir M.,Ward, Karen M.,Wetsel, William C.,Liu, Jing,Roth, Bryan L.,Jin, Jian
, p. 4755 - 4771 (2019/05/08)
Functionally selective G protein-coupled receptor ligands are valuable tools for deciphering the roles of downstream signaling pathways that potentially contribute to therapeutic effects versus side effects. Recently, we discovered both Gi/o-bi
