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

[Image: see text] Trypanosoma bruceiN-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

Forecasting Bond Risk Premia Using Technical Analysis

This paper is selected as one of the Top Ten Paper in Forecasting in SSRN

Software Startup Education : Gamifying Growth Hacking

Marketing is a vital activity for software startups as they seek high growth. A specific type of digital marketing, growth hacking, in particular has attracted a lot of attention in software startups. Growth hacking is about utilizing low-cost marketing practices and existing platforms to rapidly increase the user count of a service. Though topics related to growth hacking such as marketing on a general level have been extensively studied in the past, growth hacking has not seen much direct interest in the academia thus far. As a result, we currently have few tools to teach growth hacking in startup education. In this chapter, we present two board games intended to serve as an introduction to growth hacking.peerReviewe