Irreversible
covalent inhibitors can have a beneficial pharmacokinetic/pharmacodynamics
profile but are still often avoided due to the risk of indiscriminate
covalent reactivity and the resulting adverse effects. To overcome
this potential liability, we introduced an alkyne moiety as a latent
electrophile into small molecule inhibitors of cathepsin K (CatK).
Alkyne-based inhibitors do not show indiscriminate thiol reactivity
but potently inhibit CatK protease activity by formation of an irreversible
covalent bond with the catalytic cysteine residue, confirmed by crystal
structure analysis. The rate of covalent bond formation (
k
inact
) does not correlate with electrophilicity of the
alkyne moiety, indicative of a proximity-driven reactivity. Inhibition
of CatK-mediated bone resorption is validated in human osteoclasts.
Together, this work illustrates the potential of alkynes as latent
electrophiles in small molecule inhibitors, enabling the development
of irreversible covalent inhibitors with an improved safety profile.
Poly (ADP−ribose) polymerase (PARP) inhibitors are a relatively new class of anticancer agents that have attracted attention for treatment of glioblastoma because of their ability to potentiate temozolomide chemotherapy. Previous studies have demonstrated that sufficient brain penetration is a prerequisite for efficacy of PARP inhibitors in glioma mouse models. Unfortunately, however, most of the PARP inhibitors developed to date have a limited brain penetration due to the presence of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) at the blood−brain barrier. AZD2461 is a novel PARP inhibitor that is unaffected by P-gp mediated resistance in breast cancer models and thus appears to have promising characteristics for brain penetration. We here use a comprehensive set of in vitro and in vivo models to study the brain penetration and oral bioavailability of AZD2461. We report that AZD2461 has a good membrane permeability. However, it is a substrate of P-gp and BCRP, and P-gp in particular limits its brain penetration in vivo. We show that AZD2461 has a low oral bioavailability, although it is not affected by P-gp and BCRP. Together, these findings are not in favor of further development of AZD2461 for treatment of glioblastoma.
The reagent 2-chloro-5,6-benzo-l,3,2-dioxaphosphin-4-one proved to be suitable for the preparation of an anomerically ( a ) pure hydrogenphosphonate as well as a phosphite-triester. The former could be applied for the formation of an interglycosidic hydrogenphosphonate linkage.
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