Anthelmintics Derived from the Kinase Inhibitor SGI-1776 for the Treatment of Gastrointestinal Worm Infections.

Abstract

Human gastrointestinal nematodes (GINs) infect at least one billion people, mostly children, with five billion people at risk of infection. Reduced and low efficacy of currently used anthelmintics, e.g., benzimidazoles against Trichuris trichiura whipworms, urges new anthelmintics to control these parasites. We previously discovered two human pan-PIM kinase inhibitors, CX-6258 and SGI-1776, with potent antihelmintic activity against GINs. Here, structure-activity relationship (SAR) studies were conducted to identify SGI-1776 analogs with improved cross-clade adulticidal activity (Ancylostoma ceylanicum hookworms and Trichuris muris whipworms). We further identified a new chemical series from 15 (imidazo[1,2-b]pyridazine-3-carboxamide) and novel derivatives from it. Differential cuticle permeability, quantified by the amount of bioaccumulated drugs, explained some unexpected observations regarding activity and correlated with their physicochemical properties. The compounds' physical properties were significantly predictive of their activity. 15 and 51 were the most potent against whipworm and showed decreased and no activity against human PIM kinases, suggesting increased selectivity against the GIN counterparts. The unexpected SAR of compound 15 can be explained by computational modeling. We demonstrate the efficacy of optimized compound 50 as a new oral anthelmintic, which demonstrated better gut restriction properties and significantly reduced the fecundity of T. muris whipworm adults in infected mice. We also report our findings on physicochemical properties and gut restriction ADME parameters that are essential for further lead optimization.