{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Brand S"],"funding":["Medical Research Council","Wellcome Trust"],"pagination":["9855-69"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC4269550"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["57(23)"],"pubmed_abstract":["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-brain barrier permeability, achieved by reducing polar surface area and capping the sulfona"],"journal":["Journal of medicinal chemistry"],"pubmed_title":["Lead optimization of a pyrazole sulfonamide series of Trypanosoma brucei N-myristoyltransferase inhibitors: identification and evaluation of CNS penetrant compounds as potential treatments for stage 2 human African trypanosomiasis."],"pmcid":["PMC4269550"],"funding_grant_id":["079838","WT077705","MR/M004139/1","092340","WT083481","087590","G0900138","101842","101842/Z/13/Z","WT085622"],"pubmed_authors":["Smith VC","McElroy SP","Brenk R","Simeons FR","Norval S","Torrie LS","Scullion P","Frearson JA","Wyatt PG","Thompson S","Fairlamb AH","Brand S","Robinson DA","Gilbert IH","Norcross NR","Harrison JR","Hallyburton I","Ferguson MA","van Aalten D","Read KD","Stojanovski L"],"additional_accession":[]},"is_claimable":false,"name":"Lead optimization of a pyrazole sulfonamide series of Trypanosoma brucei N-myristoyltransferase inhibitors: identification and evaluation of CNS penetrant compounds as potential treatments for stage 2 human African trypanosomiasis.","description":"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-brain barrier permeability, achieved by reducing polar surface area and capping the sulfona","dates":{"release":"2014-01-01T00:00:00Z","publication":"2014 Dec","modification":"2026-05-02T05:29:21.088Z","creation":"2019-03-27T01:41:57Z"},"accession":"S-EPMC4269550","cross_references":{"pubmed":["25412409"],"doi":["10.1021/jm500809c"]}}