95649-37-9Relevant articles and documents
Probing the substitution pattern of indole-based scaffold reveals potent and selective sphingosine kinase 2 inhibitors
Congdon, Molly,Fritzemeier, Russell G.,Kharel, Yugesh,Brown, Anne M.,Serbulea, Vlad,Bevan, David R.,Lynch, Kevin R.,Santos, Webster L.
, (2021/01/18)
Elevated levels of sphingosine 1-phosphate (S1P) and increased expression of sphingosine kinase isoforms (SphK1 and SphK2) have been implicated in a variety of disease states including cancer, inflammation, and autoimmunity. Consequently, the S1P signaling axis has become an attractive target for drug discovery. Selective inhibition of either SphK1 or SphK2 has been demonstrated to be effective in modulating S1P levels in animal models. While SphK1 inhibitors have received much attention, the development of potent and selective SphK2 inhibitors are emerging. Previously, our group reported a SphK2 naphthalene-based selective inhibitor, SLC5081308, which displays approximately 7-fold selectivity for hSphK2 over hSphK1 and has a SphK2 Ki value of 1.0 μM. To improve SphK2 potency and selectivity, we designed, synthesized, and evaluated a series of indole-based compounds derived from SLC5081308. After investigating substitution patterns around the indole ring, we discovered that 1,5-disubstitution promoted optimal binding in the SphK2 substrate binding site and subsequent inhibition of enzymatic activity. Our studies led to the identification of SLC5101465 (6r, SphK2 Ki = 90 nM, >110 fold selective for SphK2 over SphK1). Molecular modeling studies revealed key nonpolar interactions with Val308, Phe548, His556, and Cys533 and hydrogen bonds with both Asp211 and Asp308 as responsible for the high SphK2 inhibition and selectivity.
Room-temperature synthesis of pharmaceutically important carboxylic acids bearing the 1,2,4-oxadiazole moiety
Tarasenko, Marina,Duderin, Nikolay,Sharonova, Tatyana,Baykov, Sergey,Shetnev, Anton,Smirnov, Alexey V.
supporting information, p. 3672 - 3677 (2017/08/23)
An efficient and mild one-pot protocol has been developed for the synthesis of 1,2,4-oxadiazoles via the reaction of amidoximes with dicarboxylic acid anhydrides in a NaOH/DMSO medium. The method allows the synthesis of diversely substituted carboxylic acids bearing the 1,2,4-oxadiazole motif, – a popular building block for pharmaceutical research, in moderate to excellent yields. The reaction scope includes aromatic and heteroaromatic amidoximes as well as five-, six- and seven-membered anhydrides. The advantages of this procedure are proven gram-scalability and the use of inexpensive starting materials, which from a process chemistry point of view are essential for future industrial applications.
SYNTHESIS OF FUNCTIONAL DERIVATIVES OF INDOLE-3-CARBOXYLIC ACIDS
Kelarev, V. I.,Gasanov, S. Sh.,Karakhanov, R. A.,Polivin, Yu. N.,Kuatbekova, K. P.,Panina, M. E.
, p. 2069 - 2074 (2007/10/02)
Methods are described for the synthesis of the esters, hydrazides, amidines, N-phenylamidines, N1-phenylamidrazones, N1-acylamidrazones, and amide oximes of indole-3-carboxylic and 1-methylindole-3-carboxylic acids.
