NEU-1953 is a compound that is an advanced lead for human African trypanosomiasis. Its potency is in a reasonable (not excellent) range, but the bigger issue at hand is that its aqueous solubility is poor (44 uM; target >100 uM) and its in vitro metabolic clearance is rapid (microsomal clearance: 180 uL/min/mg, target <47); hepatocyte clearance: 127 uL/min/106 cells; target <28). Physicochemical and metabolic properties are often far more important than compound potency when testing in vivo, and so we need to improve solubility and clearance.
(1) What strategies would you consider implementing that can improve aqueous solubility and reduce clearance?
(2) What synthetic route would you use to make the compounds you propose?
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Compound A and B are suggested targets, these two can lower the cLogP and LogD values. The compound NEU-1953 has 8 nitrogen atoms and all are in the ring, so that they are sterically not favorable to approach water molecules, polar groups away from the main core increase the solubility. I think, metabolic clearance can be reduced if hydrogen substituted with some polar chain group of NH attached to quino lone....

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