{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T23:13:33Z","timestamp":1788390813209,"version":"build-2803163510"},"reference-count":34,"publisher":"American Chemical Society (ACS)","issue":"23","license":[{"start":{"date-parts":[[2014,12,2]],"date-time":"2014-12-02T00:00:00Z","timestamp":1417478400000},"content-version":"vor","delay-in-days":12,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_ccby_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["WT077705"],"award-info":[{"award-number":["WT077705"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["WT083481"],"award-info":[{"award-number":["WT083481"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["WT085622"],"award-info":[{"award-number":["WT085622"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,12,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Trypanosoma brucei N-myristoyltransferase (TbNMT) is an attractive therapeutic target for the treatment of human African trypanosomiasis (HAT). From previous studies, we identified pyrazole sulfonamide, DDD85646 (1), a potent inhibitor of TbNMT. Although this compound represents an excellent lead, poor central nervous system (CNS) exposure restricts its use to the hemolymphatic form (stage 1) of the disease. With a clear clinical need for new drug treatments for HAT that address both the hemolymphatic and CNS stages of the disease, a chemistry campaign was initiated to address the shortfalls of this series. This paper describes modifications to the pyrazole sulfonamides which markedly improved blood\u2013brain barrier permeability, achieved by reducing polar surface area and capping the sulfonamide. Moreover, replacing the core aromatic with a flexible linker significantly improved selectivity. This led to the discovery of DDD100097 (40) which demonstrated partial efficacy in a stage 2 (CNS) mouse model of HAT.<\/jats:p>","DOI":"10.1021\/jm500809c","type":"journal-article","created":{"date-parts":[[2014,11,20]],"date-time":"2014-11-20T15:57:49Z","timestamp":1416499069000},"page":"9855-9869","source":"Crossref","is-referenced-by-count":70,"title":["Lead Optimization of a Pyrazole\nSulfonamide Series\nof\n                    <i>Trypanosoma brucei<\/i>\n                    <i>N<\/i>\n                    -Myristoyltransferase Inhibitors: Identification and Evaluation\nof CNS Penetrant Compounds as Potential Treatments for Stage 2 Human\nAfrican Trypanosomiasis"],"prefix":"10.1021","volume":"57","author":[{"given":"Stephen","family":"Brand","sequence":"first","affiliation":[{"name":"University of Dundee , , Sir James Black Centre , ,","place":["Dundee, U.K., DD1 5EH"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil R.","family":"Norcross","sequence":"additional","affiliation":[{"name":"University of Dundee , , Sir James Black Centre , ,","place":["Dundee, U.K., DD1 5EH"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Thompson","sequence":"additional","affiliation":[{"name":"University of Dundee , , Sir James Black Centre , ,","place":["Dundee, U.K., DD1 5EH"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin R.","family":"Harrison","sequence":"additional","affiliation":[{"name":"University of Dundee , , Sir James Black Centre , ,","place":["Dundee, U.K., DD1 5EH"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria C.","family":"Smith","sequence":"additional","affiliation":[{"name":"University of Dundee , , Sir James Black Centre , ,","place":["Dundee, U.K., DD1 5EH"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Robinson","sequence":"additional","affiliation":[{"name":"University of Dundee , , Sir James Black Centre , ,","place":["Dundee, U.K., DD1 5EH"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah S.","family":"Torrie","sequence":"additional","affiliation":[{"name":"University of Dundee , , Sir James Black Centre , ,","place":["Dundee, U.K., DD1 5EH"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart P.","family":"McElroy","sequence":"additional","affiliation":[{"name":"University of Dundee , , Sir James Black Centre , ,","place":["Dundee, U.K., DD1 5EH"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Hallyburton","sequence":"additional","affiliation":[{"name":"University of Dundee , , Sir James Black Centre , ,","place":["Dundee, U.K., DD1 5EH"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne","family":"Norval","sequence":"additional","affiliation":[{"name":"University of Dundee , , Sir James Black Centre , ,","place":["Dundee, U.K., DD1 5EH"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Scullion","sequence":"additional","affiliation":[{"name":"University of Dundee , , Sir James Black Centre , ,","place":["Dundee, U.K., DD1 5EH"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laste","family":"Stojanovski","sequence":"additional","affiliation":[{"name":"University of Dundee , , Sir James Black Centre , ,","place":["Dundee, U.K., DD1 5EH"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick R. C.","family":"Simeons","sequence":"additional","affiliation":[{"name":"University of Dundee , , Sir James Black Centre , ,","place":["Dundee, U.K., DD1 5EH"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daan","family":"van Aalten","sequence":"additional","affiliation":[{"name":"University of Dundee , , Sir James Black Centre , ,","place":["Dundee, U.K., DD1 5EH"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie A.","family":"Frearson","sequence":"additional","affiliation":[{"name":"University of Dundee , , Sir James Black Centre , ,","place":["Dundee, U.K., DD1 5EH"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Brenk","sequence":"additional","affiliation":[{"name":"University of Dundee , , Sir James Black Centre , ,","place":["Dundee, U.K., DD1 5EH"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan H.","family":"Fairlamb","sequence":"additional","affiliation":[{"name":"University of Dundee , , Sir James Black Centre , ,","place":["Dundee, U.K., DD1 5EH"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A. J.","family":"Ferguson","sequence":"additional","affiliation":[{"name":"University of Dundee , , Sir James Black Centre , ,","place":["Dundee, U.K., DD1 5EH"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul G.","family":"Wyatt","sequence":"additional","affiliation":[{"name":"University of Dundee , , Sir James Black Centre , ,","place":["Dundee, U.K., DD1 5EH"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian H.","family":"Gilbert","sequence":"additional","affiliation":[{"name":"University of Dundee , , Sir James Black Centre , ,","place":["Dundee, U.K., DD1 5EH"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin D.","family":"Read","sequence":"additional","affiliation":[{"name":"University of Dundee , , Sir James Black Centre , ,","place":["Dundee, U.K., DD1 5EH"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,11,20]]},"reference":[{"key":"2026090218171431800_cit1","doi-asserted-by":"crossref","first-page":"677","DOI":"10.2217\/fmb.11.44","article-title":"Development of novel\ndrugs for human African trypanosomiasis","volume":"6","author":"Brun","year":"2011","journal-title":"Future\nMicrobiol."},{"key":"2026090218171431800_cit2","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1172\/JCI33945","article-title":"Kinetoplastids: related\nprotozoan pathogens, different diseases","volume":"118","author":"Stuart","year":"2008","journal-title":"J.\nClin. Invest."},{"key":"2026090218171431800_cit3","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.2174\/156802611795429167","article-title":"State of the Art in African Trypanosome\nDrug Discovery","volume":"11","author":"Jacobs","year":"2011","journal-title":"Curr. Top. Med. Chem."},{"key":"2026090218171431800_cit4","doi-asserted-by":"crossref","first-page":"39501","DOI":"10.1074\/jbc.R100042200","article-title":"The biology\nand enzymology of protein N-myristoylation","volume":"276","author":"Farazi","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2026090218171431800_cit5","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1038\/nchembio834","article-title":"Trafficking\nand signaling by fatty-acylated and prenylated proteins","volume":"2","author":"Resh","year":"2006","journal-title":"Nature Chem. 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Med. Chem."},{"key":"2026090218171431800_cit15","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1038\/nature08893","article-title":"N-Myristoyltransferase inhibitors as new leads to treat\nsleeping sickness","volume":"464","author":"Frearson","year":"2010","journal-title":"Nature"},{"key":"2026090218171431800_cit16","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1023\/A:1018941328702","article-title":"Role of\nP-glycoprotein\non the CNS disposition of amprenavir (141W94), an HIV protease inhibitor","volume":"16","author":"Polli","year":"1999","journal-title":"Pharm. Res."},{"key":"2026090218171431800_cit17","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1021\/jm301297f","article-title":"Demystifying brain penetration in\ncentral nervous system drug discovery. Miniperspective","volume":"56","author":"Di","year":"2013","journal-title":"J. Med. 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Engl."},{"key":"2026090218171431800_cit21","doi-asserted-by":"crossref","first-page":"2524","DOI":"10.1021\/jm401801t","article-title":"Differences\nin conformational dynamics between Plasmodium falciparum and human Hsp90 orthologues enable the structure-based discovery\nof pathogen-selective inhibitors","volume":"57","author":"Wang","year":"2014","journal-title":"J. Med. Chem."},{"key":"2026090218171431800_cit22","doi-asserted-by":"crossref","first-page":"9224","DOI":"10.1021\/jm3009426","article-title":"Spirocyclic\nsulfamides as beta-secretase\n1 (BACE-1) inhibitors for the treatment of Alzheimer\u2019s disease:\nutilization of structure based drug design, WaterMap, and CNS penetration\nstudies to identify centrally efficacious inhibitors","volume":"55","author":"Brodney","year":"2012","journal-title":"J. Med. 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London B, Biol. Sci."},{"key":"2026090218171431800_cit26","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1517\/17425250903559873","article-title":"Assessing brain free\nfraction in early drug discovery","volume":"6","author":"Read","year":"2010","journal-title":"Expert. Opin.\nDrug. Metab. Toxicol."},{"key":"2026090218171431800_cit27","doi-asserted-by":"crossref","first-page":"4872","DOI":"10.1016\/j.bmcl.2008.07.071","article-title":"Physiochemical\ndrug properties associated with in vivo toxicological outcomes","volume":"18","author":"Hughes","year":"2008","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"2026090218171431800_cit28","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1042\/BJ20051886","article-title":"Characterization and selective inhibition\nof myristoyl-CoA: protein N-myristoyltransferase\nfrom Trypanosoma brucei and Leishmania major","volume":"396","author":"Panethymitaki","year":"2006","journal-title":"Biochem.\nJ."},{"key":"2026090218171431800_cit29","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/S0001-706X(97)00079-X","article-title":"The Alamar\nBlue assay to determine drug sensitivity of African trypanosomes (T. b. rhodesiense and T. b. gambiense) in vitro","volume":"68","author":"Raz","year":"1997","journal-title":"Acta Trop."},{"key":"2026090218171431800_cit30","doi-asserted-by":"crossref","first-page":"985","DOI":"10.2307\/3282883","article-title":"Continuous cultivation of Trypanosoma brucei blood stream forms in a medium containing a\nlow concentration of serum-protein without feeder cell-layers","volume":"75","author":"Hirumi","year":"1989","journal-title":"J. Parasitol."},{"key":"2026090218171431800_cit31","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1046\/j.1365-3156.1996.d01-46.x","article-title":"Topical chemotherapy\nfor experimental African trypanosomiasis with cerebral involvement:\nthe use of melarsoprol combined with the 5-nitroimidazole, megazol","volume":"1","author":"Jennings","year":"1996","journal-title":"Trop. Med. Int. Health"},{"key":"2026090218171431800_cit32","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1111\/j.1471-4159.2008.05706.x","article-title":"The blood\u2013brain\nbarrier significantly limits eflornithine entry into Trypanosoma brucei brucei infected mouse brain","volume":"107","author":"Sanderson","year":"2008","journal-title":"J. Neurochem."},{"key":"2026090218171431800_cit33","first-page":"147","article-title":"Relapsed parasitaemia following chemotherapy of chronic T. brucei infections in mice and its relation to\ncerebral trypanosomes","volume":"7","author":"Jennings","year":"1983","journal-title":"Contrib. Microbiol. 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