ddd-85646 and Trypanosomiasis--African

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.

Topics: Acyltransferases; Aminopyridines; Animals; Brain; Crystallography, X-Ray; Drug Design; Enzyme Inhibitors; Humans; Mice; Sulfonamides; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosomiasis, African

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.

Topics: Acyltransferases; Aminopyridines; Animals; Blood-Brain Barrier; Central Nervous System; Female; Humans; Inhibitory Concentration 50; Mice; Pyrazoles; Structure-Activity Relationship; Sulfonamides; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosomiasis, African

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.

Topics: Acyltransferases; Administration, Oral; Aminopyridines; Animals; Cell Line; Cell Survival; Crystallography, X-Ray; Databases, Factual; Humans; Models, Molecular; Molecular Conformation; Parasitic Sensitivity Tests; Structure-Activity Relationship; Sulfonamides; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosomiasis, African

Topics: Acyltransferases; Aminopyridines; Animals; Antiparasitic Agents; Enzyme Inhibitors; Humans; Mice; Sulfonamides; Trypanosoma brucei brucei; Trypanosomiasis, African

African sleeping sickness or human African trypanosomiasis, caused by Trypanosoma brucei spp., is responsible for approximately 30,000 deaths each year. Available treatments for this disease are poor, with unacceptable efficacy and safety profiles, particularly in the late stage of the disease when the parasite has infected the central nervous system. Here we report the validation of a molecular target and the discovery of associated lead compounds with the potential to address this lack of suitable treatments. Inhibition of this target-T. brucei N-myristoyltransferase-leads to rapid killing of trypanosomes both in vitro and in vivo and cures trypanosomiasis in mice. These high-affinity inhibitors bind into the peptide substrate pocket of the enzyme and inhibit protein N-myristoylation in trypanosomes. The compounds identified have promising pharmaceutical properties and represent an opportunity to develop oral drugs to treat this devastating disease. Our studies validate T. brucei N-myristoyltransferase as a promising therapeutic target for human African trypanosomiasis.

Topics: Acyltransferases; Aminopyridines; Animals; Antiparasitic Agents; Enzyme Assays; Enzyme Inhibitors; Female; Humans; Mice; Molecular Structure; Pyrazoles; Rats; Sulfonamides; Time Factors; Trypanosoma brucei brucei; Trypanosomiasis, African