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.
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 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.
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , Sir James Black Centre, Dundee DD1 5EH, U.K.
authors.forename: Stephen
authors.initials: S
authors.lastname: Brand
authors.forename: Neil R
authors.initials: NR
authors.lastname: Norcross
authors.forename: Stephen
authors.initials: S
authors.lastname: Thompson
authors.forename: Justin R
authors.initials: JR
authors.lastname: Harrison
authors.forename: Victoria C
authors.initials: VC
authors.lastname: Smith
authors.forename: David A
authors.initials: DA
authors.lastname: Robinson
authors.forename: Leah S
authors.initials: LS
authors.lastname: Torrie
authors.forename: Stuart P
authors.initials: SP
authors.lastname: McElroy
authors.forename: Irene
authors.initials: I
authors.lastname: Hallyburton
authors.forename: Suzanne
authors.initials: S
authors.lastname: Norval
authors.forename: Paul
authors.initials: P
authors.lastname: Scullion
authors.forename: Laste
authors.initials: L
authors.lastname: Stojanovski
authors.forename: Frederick R C
authors.initials: FR
authors.lastname: Simeons
authors.forename: Daan
authors.initials: D
authors.lastname: van Aalten
authors.forename: Julie A
authors.initials: JA
authors.lastname: Frearson
authors.forename: Ruth
authors.initials: R
authors.lastname: Brenk
authors.forename: Alan H
authors.initials: AH
authors.lastname: Fairlamb
authors.forename: Michael A J
authors.initials: MA
authors.lastname: Ferguson
authors.forename: Paul G
authors.initials: PG
authors.lastname: Wyatt
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Read
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000631:Aminopyridines / Q000737:chemistry; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects; D014353:Trypanosomiasis, African / Q000188:drug therapy*; D000096926:Benzenesulfonamides
chemical_list: D000217:Acyltransferases; D000631:Aminopyridines; D011720:Pyrazoles; D013449:Sulfonamides; D014344:Trypanocidal Agents; C000595387:2,6-dichloro-N-(difluoromethyl)-4-(3-(1-methylpiperidin-4-yl)propyl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C549249:DDD 85646; C050480:glycylpeptide N-tetradecanoyltransferase