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

Stephen Brand, Neil R. Norcross, Stephen Thompson, Justin R. Harrison, Victoria C. Smith, David A. Robinson, Leah S. Torrie, Stuart P. McElroy, Irene Hallyburton, Suzanne Norval, Paul Scullion, Laste Stojanovski, Frederick R.C. Simeons, Daan Van Aalten, Julie A. Frearson, Ruth Brenk, Alan H. Fairlamb, Michael A.J. Ferguson, Paul G. Wyatt, Ian H. GilbertKevin D. Read

Research output: Contribution to journalArticle

30 Citations (Scopus)
54 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)9855-9869
Number of pages15
JournalJournal of Medicinal Chemistry
Volume57
Issue number23
Early online date20 Nov 2014
DOIs
Publication statusPublished - 11 Dec 2014

Fingerprint

African Trypanosomiasis
Trypanosoma brucei brucei
Sulfonamides
Central Nervous System
Neurologic Mutant Mice
Central Nervous System Diseases
Blood-Brain Barrier
Permeability
Pharmaceutical Preparations
pyrazole
glycylpeptide N-tetradecanoyltransferase
Lead
Therapeutics

Cite this

@article{9f797e85d1844bbd82a92036110cceb1,
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.",
author = "Stephen Brand and Norcross, {Neil R.} and Stephen Thompson and Harrison, {Justin R.} and Smith, {Victoria C.} and Robinson, {David A.} and Torrie, {Leah S.} and McElroy, {Stuart P.} and Irene Hallyburton and Suzanne Norval and Paul Scullion and Laste Stojanovski and Simeons, {Frederick R.C.} and {Van Aalten}, Daan and Frearson, {Julie A.} and Ruth Brenk and Fairlamb, {Alan H.} and Ferguson, {Michael A.J.} and Wyatt, {Paul G.} and Gilbert, {Ian H.} and Read, {Kevin D.}",
year = "2014",
month = "12",
day = "11",
doi = "10.1021/jm500809c",
language = "English",
volume = "57",
pages = "9855--9869",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "23",

}

TY - JOUR

T1 - Lead optimization of a pyrazole sulfonamide series of trypanosoma brucei N -myristoyltransferase inhibitors

T2 - Identification and evaluation of CNS penetrant compounds as potential treatments for stage 2 human african trypanosomiasis

AU - Brand, Stephen

AU - Norcross, Neil R.

AU - Thompson, Stephen

AU - Harrison, Justin R.

AU - Smith, Victoria C.

AU - Robinson, David A.

AU - Torrie, Leah S.

AU - McElroy, Stuart P.

AU - Hallyburton, Irene

AU - Norval, Suzanne

AU - Scullion, Paul

AU - Stojanovski, Laste

AU - Simeons, Frederick R.C.

AU - Van Aalten, Daan

AU - Frearson, Julie A.

AU - Brenk, Ruth

AU - Fairlamb, Alan H.

AU - Ferguson, Michael A.J.

AU - Wyatt, Paul G.

AU - Gilbert, Ian H.

AU - Read, Kevin D.

PY - 2014/12/11

Y1 - 2014/12/11

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84918563084&partnerID=8YFLogxK

U2 - 10.1021/jm500809c

DO - 10.1021/jm500809c

M3 - Article

C2 - 25412409

AN - SCOPUS:84918563084

VL - 57

SP - 9855

EP - 9869

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 23

ER -