Discovery of uncharted guanidinium peptide coupling reagent side reactions during peptide-drug conjugates synthesis.

Neglected tropical diseases such as human African trypanosomiasis (HAT) are prevalent primarily in tropical climates and among populations living in poverty. Historically, the lack of economic incentive to develop new treatments for these diseases has meant that existing therapeutics have serious shortcomings in terms of safety, efficacy, and administration, and better therapeutics are needed. We now report a series of 3,5-disubstituted-7-azaindoles identified as growth inhibitors of Trypanosoma brucei, the parasite that causes HAT, through a high-throughput screen. We describe the hit-to-lead optimization of this series and the development and preclinical investigation of 29d, a potent anti-trypanosomal compound with promising pharmacokinetic (PK) parameters. This compound was ultimately not progressed beyond in vivo PK studies due to its inability to penetrate the blood-brain barrier (BBB), critical for stage 2 HAT treatments. Targeted Value NEU-1207 NEU-1208 NEU-1209 T.b.b. pEC50 ≥7 7.0 7.2 6.5 HepG2 pTC50 ≤pEC50-2 4.5 5.0 4.0 cLogP ≤3 2.6 2.8 2.2 TPSA (Å 2 ) 4010 2 18 † 12 † PPB (%) <95 95 nd nd

Structure–property and structure–activity studies identify regions that positively modulate aqueous solubility; though maintaining potent anti-trypanosomal potency proves challenging.