Selectivity and Physicochemical Optimization of Repurposed Pyrazolo[1,5-<i>b</i>]pyridazines for the Treatment of Human African Trypanosomiasis

Abstract

From a high-throughput screen of 42 444 known human kinases inhibitors, a pyrazolo[1,5-<i>b</i>]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 <b>23a</b> which showed selectivity for <i>T. b. brucei</i> 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 <b>20g</b> being progressed into an efficacy study in mice. Though <b>20g</b> 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.