Abstract
From a high-throughput screen of 42 444 known human kinases inhibitors, a pyrazolo[1,5-b]pyridazine scaffold was identified to begin optimization for the treatment of human African trypanosomiasis. Previously reported data for analogous compounds against human kinases GSK-3β, CDK-2, and CDK-4 were leveraged to try to improve the selectivity of the series, resulting in 23a which showed selectivity for T. b. brucei over these three human enzymes. In parallel, properties known to influence the absorption, distribution, metabolism, and excretion (ADME) profile of the series were optimized resulting in 20g being progressed into an efficacy study in mice. Though 20g showed toxicity in mice, it also demonstrated CNS penetration in a PK study and significant reduction of parasitemia in four out of the six mice.
Highlights
Human African trypanosomiasis (HAT), or sleeping sickness as it is commonly referred to, is a parasitic disease caused by two subspecies of Trypanosoma brucei.[1]
In order to assess the difference in compound potency between T. b. brucei and glycogen synthase kinase 3β (GSK-3β), cyclin dependent kinases (CDK)-2, and CDK
4, we evaluated previously reported compounds from the original high-throughput screen (HTS) with potency data against the three human kinases to see if we could find any difference in the selectivity profiles.[26,31]
Summary
Human African trypanosomiasis (HAT), or sleeping sickness as it is commonly referred to, is a parasitic disease caused by two subspecies of Trypanosoma brucei.[1]. Substitution at the R2 position with a morpholine or methoxy had previously shown a reduction in activity versus human CDK-2 and CDK-4; as such, we wanted to assess whether these substituents could help improve the ADME properties of the series (Table 8). Comparison of 23g and 23l to their matched pair analogs with no substitution at the R1 position (23e and 23k, respectively) showed no decrease in potency This trend was not observed with compounds containing a morpholine group at the R2 position, as 23h was over 10-fold less active than its unsubstituted matched pair 23i. This increase in potency from the introduction of a methoxy group can be observed comparing 21d (Table 7) to 23a, where 23a was 4-fold more active. Apart from these two compounds, this cluster does not warrant further investigation as a source of antischistosomal agents
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