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. Gilbert; Kevin D. Read

doi:10.1021/jm500809c

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

Biological Chemistry and Drug Discovery

Research output: Contribution to journal › Article › peer-review

62 Citations (Scopus)

181 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 language	English
Pages (from-to)	9855-9869
Number of pages	15
Journal	Journal of Medicinal Chemistry
Volume	57
Issue number	23
Early online date	20 Nov 2014
DOIs	https://doi.org/10.1021/jm500809c
Publication status	Published - 11 Dec 2014

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Dive into the research topics of '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'. Together they form a unique fingerprint.

Genetic Structural and Chemical Validation of Aspergillus Fumigatus Cell Wall Targets (Programme Grant)
van Aalten, D. (Investigator)
Medical Research Council
1/11/14 → 31/10/19
Project: Research
Protein Glycosylation in Trypanosomes: Defining and Exploiting a Biological System (Senior Investigator Award)
Ferguson, M. (Investigator)
1/10/13 → 30/06/23
Project: Research
Discovery and Development of Drug Candidates for Neglected Diseases (joint with industrial partner)
Brenk, R. (Investigator), Fairlamb, A. (Investigator), Ferguson, M. (Investigator), Field, M. (Investigator), Gilbert, I. (Investigator), Gray, D. (Investigator), Hopkins, A. (Investigator), Horn, D. (Investigator), Read, K. (Investigator), Wyatt, P. (Investigator) & van Aalten, D. (Investigator)
1/02/11 → 1/07/17
Project: Research

Read, Kevin
- Drug Discovery Unit - Professor of Quantitative Pharmacology
Person: Academic

Cite this

Brand, S., Norcross, N. R., Thompson, S., Harrison, J. R., Smith, V. C., Robinson, D. A., Torrie, L. S., McElroy, S. P., Hallyburton, I., Norval, S., Scullion, P., Stojanovski, L., Simeons, F. R. C., Van Aalten, D., Frearson, J. A., Brenk, R., Fairlamb, A. H., Ferguson, M. A. J., Wyatt, P. G., ... Read, K. D. (2014). 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. Journal of Medicinal Chemistry, 57(23), 9855-9869. https://doi.org/10.1021/jm500809c

Brand, Stephen ; Norcross, Neil R. ; Thompson, Stephen et al. / 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. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 23. pp. 9855-9869.

@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 = dec,

day = "11",

doi = "10.1021/jm500809c",

language = "English",

volume = "57",

pages = "9855--9869",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

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Brand, S, Norcross, NR, Thompson, S , Harrison, JR, Smith, VC, Robinson, DA, Torrie, LS, McElroy, SP, Hallyburton, I , Norval, S, Scullion, P, Stojanovski, L , Simeons, FRC , Van Aalten, D, Frearson, JA, Brenk, R, Fairlamb, AH , Ferguson, MAJ, Wyatt, PG, Gilbert, IH & Read, KD 2014, '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', Journal of Medicinal Chemistry, vol. 57, no. 23, pp. 9855-9869. https://doi.org/10.1021/jm500809c

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. / Brand, Stephen; Norcross, Neil R.; Thompson, Stephen et al.
In: Journal of Medicinal Chemistry, Vol. 57, No. 23, 11.12.2014, p. 9855-9869.

Research output: Contribution to journal › Article › peer-review

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.

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Brand S, Norcross NR, Thompson S , Harrison JR, Smith VC, Robinson DA et al. 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. Journal of Medicinal Chemistry. 2014 Dec 11;57(23):9855-9869. Epub 2014 Nov 20. doi: 10.1021/jm500809c

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

ASJC Scopus subject areas

UN SDGs

Access to Document

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Projects

Genetic Structural and Chemical Validation of Aspergillus Fumigatus Cell Wall Targets (Programme Grant)

Protein Glycosylation in Trypanosomes: Defining and Exploiting a Biological System (Senior Investigator Award)

Discovery and Development of Drug Candidates for Neglected Diseases (joint with industrial partner)

Profiles

Read, Kevin

Cite this