Cathepsin S (Cat S) plays an important role in many pathological conditions, including abdominal aortic aneurysm (AAA). Inhibition of Cat S may provide a new treatment for AAA. To date, several classes of Cat S inhibitors have been reported, many of which form covalent interactions with the active site Cys25. Herein, we report the discovery of a novel series of noncovalent inhibitors of Cat S through a medium-throughput focused cassette screen and the optimization of the resulting hits. Structure-based optimization efforts led to Cat S inhibitors such as 5 and 9 with greatly improved potency and drug disposition properties. This series of compounds binds to the S2 and S3 subsites without interacting with the active site Cys25. On the basis of in vitro potency, selectivity, and efficacy in a CaCl2-induced AAA in vivo model, 5 (LY3000328) was selected for clinical development.
4-Methoxyphenylbutyric acid (2) is smoothly demethylated in
3 h at 180 °C when melted with pyridinium hydrochloride (Pyr·HCl), affording 4-hydroxyphenylbutyric acid (3), a key starting
material for the preclinical candidate LY518674 (1). The
adaptation of this chemistry to 22-L and pilot-plant scale is
described, including findings to facilitate product isolation,
selection of a compatible extraction solvent, and observation
of an unusual relationship between the number of solvent
extractions and the Pyr·HCl stoichiometry. To the best of our
knowledge, this represents the first literature report of the use
of this classic demethylation chemistry on multikilogram scale.
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