- Development of small-molecule Trypanosoma brucei N-myristoyltransferase inhibitors: Discovery and optimisation of a novel binding mode
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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.
- 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.
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- MERTK DEGRADERS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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Paragraph 00803
(2020/01/31)
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- N-(3-(7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL)PHENYL)BENZAMIDE DERIVATIVES
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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.
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Page/Page column 87; 88
(2019/10/23)
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- 3-HYDROXY-N-(3-(7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL)PHENYL)PYRROLIDINE-1-CARBOXAMIDE DERIVATIVES
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The invention relates to compounds of the formula (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 compris
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Page/Page column 70
(2019/10/23)
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- CETP INHIBITORS
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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
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Page/Page column 52
(2008/06/13)
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- Novel Compounds
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Compounds of Formulae I, or pharmaceutically acceptable salts thereof: wherein X, R1, R2 and R3 are as defined in the specification as well as salts and pharmaceutical compositions including the compounds are prepared. They are useful in therapy, in particular in the management of pain.
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Page/Page column 60
(2008/06/13)
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- Cyclic hexapeptides having antibiotic activity
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This invention relates to new polypeptide compound represented by general formula (I), wherein R1, R2, R3, R4, R5 and R6 are as defined in the description or a salt thereof which has antimicrobial activities (especially, antifungal activities), inhibitory activity on β-1,3-glucan synthase, to process for preparation thereof, to a pharmaceutical composition comprising the same, and to a method for prophylactic and/or therapeutic treatment of infectious diseases including Pneumocystis carinii infection (e.g. Pneumocystis carinii pneumonia) in a human being or an animal.
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- Benzimidazolidinone derivatives as muscarinic agents
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Benzimidazolidinone derivative compounds, which increase acetylcholine signaling or effect in the brain, and highly selective muscarinic agonists, particularly for the M1 and/or M4 receptor subtypes, pharmaceutical compositions comprising the same, as well as methods of treating psychosis using these compounds are disclosed.
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Page/Page column 15
(2010/02/06)
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- Fibrinogen receptor antagonists
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Novel fibrinogen receptor antagonists of the formula: are provided in which the claimed compounds exhibit fibrinogen receptor antagonist activity, inhibit platelet aggregation and are therefore useful in modulating thrombus formation.
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