163210-43-3Relevant articles and documents
Development of small-molecule Trypanosoma brucei N-myristoyltransferase inhibitors: Discovery and optimisation of a novel binding mode
Spinks, Daniel,Smith, Victoria,Thompson, Stephen,Robinson, David A.,Luksch, Torsten,Smith, Alasdair,Torrie, Leah S.,McElroy, Stuart,Stojanovski, Laste,Norval, Suzanne,Collie, Iain T.,Hallyburton, Irene,Rao, Bhavya,Brand, Stephen,Brenk, Ruth,Frearson, Julie A.,Read, Kevin D.,Wyatt, Paul G.,Gilbert, Ian H.
, p. 1821 - 1836 (2015)
The enzyme N-myristoyltransferase (NMT) from Trypanosoma brucei has been validated both chemically and biologically as a potential drug target for human African trypanosomiasis. We previously reported the development of some very potent compounds based around a pyrazole sulfonamide series, derived from a high-throughput screen. Herein we describe work around thiazolidinone and benzomorpholine scaffolds that were also identified in the screen. An X-ray crystal structure of the thiazolidinone hit in Leishmania major NMT showed the compound bound in the previously reported active site, utilising a novel binding mode. This provides potential for further optimisation. The benzomorpholinone was also found to bind in a similar region. Using an X-ray crystallography/structure-based design approach, the benzomorpholinone series was further optimised, increasing activity against T. brucei NMT by >1000-fold. A series of trypanocidal compounds were identified with suitable in vitro DMPK properties, including CNS exposure for further development. Further work is required to increase selectivity over the human NMT isoform and activity against T. brucei. HATs off to diversity! Screening a diverse library against Trypanosoma brucei N-myristoyltransferase (NMT) identified hits based on thiazolidinone and benzomorpholine scaffolds. X-ray crystallography of these compounds bound to Leishmania major NMT revealed novel active site binding conformations. Using the structural information, the benzomorpholine scaffold was optimised to a blood-brain barrier penetrant compound with activity against TbNMT of 0.002 μm.
N-(3-(7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL)PHENYL)BENZAMIDE DERIVATIVES
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Page/Page column 87; 88, (2019/10/23)
The invention relates to compounds of the formula (I) (I) or a pharmaceutically acceptable salt thereof, wherein the substituents are as defined in the specification; to intermediates in the preparation of the compounds, to pharmaceutical compositions comprising the compounds and to use of the compounds in the treatment of disease.
CETP INHIBITORS
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Page/Page column 52, (2008/06/13)
Compounds of Formula I, including pharmaceutically acceptable salts of the compounds, are CETP inhibitors, and are useful for raising HDL-cholesterol, reducing LDL-cholesterol, and for treating or preventing atherosclerosis. I
