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3 results on '"McElroy SP"'

1. Design and Synthesis of Brain Penetrant Trypanocidal N-Myristoyltransferase Inhibitors.

Author

Bayliss T, Robinson DA, Smith VC, Brand S, McElroy SP, Torrie LS, Mpamhanga C, Norval S, Stojanovski L, Brenk R, Frearson JA, Read KD, Gilbert IH, and Wyatt PG

Subjects
Acyltransferases metabolism, Aminopyridines chemical synthesis, Aminopyridines pharmacokinetics, Animals, Brain metabolism, Crystallography, X-Ray, Drug Design, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacokinetics, Enzyme Inhibitors pharmacology, Humans, Mice, Sulfonamides chemical synthesis, Sulfonamides pharmacokinetics, Trypanocidal Agents chemical synthesis, Trypanocidal Agents pharmacokinetics, Trypanosomiasis, African metabolism, Acyltransferases antagonists & inhibitors, Aminopyridines chemistry, Aminopyridines pharmacology, Sulfonamides chemistry, Sulfonamides pharmacology, Trypanocidal Agents chemistry, Trypanocidal Agents pharmacology, Trypanosoma brucei brucei drug effects, Trypanosoma brucei brucei enzymology, Trypanosomiasis, African drug therapy
Abstract

N-Myristoyltransferase (NMT) represents a promising drug target within the parasitic protozoa Trypanosoma brucei (T. brucei), the causative agent for human African trypanosomiasis (HAT) or sleeping sickness. We have previously validated T. brucei NMT as a promising druggable target for the treatment of HAT in both stages 1 and 2 of the disease. We report on the use of the previously reported DDD85646 (1) as a starting point for the design of a class of potent, brain penetrant inhibitors of T. brucei NMT.

Published
2017
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2. 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.

Author

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 FR, van Aalten D, Frearson JA, Brenk R, Fairlamb AH, Ferguson MA, Wyatt PG, Gilbert IH, and Read KD

Subjects
Aminopyridines chemistry, Animals, Blood-Brain Barrier drug effects, Central Nervous System drug effects, Female, Humans, Inhibitory Concentration 50, Mice, Pyrazoles pharmacology, Pyrazoles therapeutic use, Structure-Activity Relationship, Sulfonamides chemistry, Sulfonamides pharmacology, Sulfonamides therapeutic use, Trypanocidal Agents pharmacology, Trypanosoma brucei brucei drug effects, Acyltransferases antagonists & inhibitors, Pyrazoles chemical synthesis, Sulfonamides chemical synthesis, Trypanocidal Agents chemical synthesis, Trypanosomiasis, African drug therapy
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.

Published
2014
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3. Discovery of a novel class of orally active trypanocidal N-myristoyltransferase inhibitors.

Author

Brand S, Cleghorn LA, McElroy SP, Robinson DA, Smith VC, Hallyburton I, Harrison JR, Norcross NR, Spinks D, Bayliss T, Norval S, Stojanovski L, Torrie LS, Frearson JA, Brenk R, Fairlamb AH, Ferguson MA, Read KD, Wyatt PG, and Gilbert IH

Subjects
Administration, Oral, Aminopyridines pharmacokinetics, Aminopyridines pharmacology, Animals, Cell Line, Cell Survival drug effects, Crystallography, X-Ray, Databases, Factual, Humans, Models, Molecular, Molecular Conformation, Parasitic Sensitivity Tests, Structure-Activity Relationship, Sulfonamides pharmacokinetics, Sulfonamides pharmacology, Trypanocidal Agents pharmacokinetics, Trypanocidal Agents pharmacology, Trypanosoma brucei brucei drug effects, Trypanosomiasis, African drug therapy, Acyltransferases antagonists & inhibitors, Aminopyridines chemical synthesis, Sulfonamides chemical synthesis, Trypanocidal Agents chemical synthesis
Abstract

N-Myristoyltransferase (NMT) represents a promising drug target for human African trypanosomiasis (HAT), which is caused by the parasitic protozoa Trypanosoma brucei. We report the optimization of a high throughput screening hit (1) to give a lead molecule DDD85646 (63), which has potent activity against the enzyme (IC(50) = 2 nM) and T. brucei (EC(50) = 2 nM) in culture. The compound has good oral pharmacokinetics and cures rodent models of peripheral HAT infection. This compound provides an excellent tool for validation of T. brucei NMT as a drug target for HAT as well as a valuable lead for further optimization.

Published
2012
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