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D. C. Tully et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5112–5117
This report summarizes the SAR of a potent series of
noncovalent cathepsin S inhibitors and highlights
changes leading to improvements in oral bioavailability.
The hydrophobic biaryl amide P3 substituent of 1, an
early lead compound, was replaced by aliphatic cyclic
ethers, resulting in compounds with improved physico-
chemical properties and in vitro rodent microsomal sta-
bility. This led to major improvements in PK with
analogs such as 21 being 36% orally bioavailable in rats.
Acknowledgments
The authors acknowledge Kirk Clark and Raviraj
Kulathila (Novartis Institutes for Biomedical Research)
for valuable discussions.
Supplementary data
˚
Figure 1. Crystal structure of cathepsin S at 1.8 A co-crystallized with
compound 37 (RCSB PDB ID: 2HH5). Protein carbon atoms are
colored yellow whilst those of the inhibitor are green, oxygens are red,
nitrogens blue, sulfurs orange, and fluorine violet. The Zn2+ ion is
colored bronze whilst the chloride anion is colored green. Hydrogen
bonds are indicated by dashed black and white lines. Figure generated
Supplementary data associated with this article can be
References and notes
that Zn2+ is not required for in vitro inhibition of Cat S
in our biochemical assays.14 This was accomplished by
adding 2 lM ZnCl2 to the assay buffer in the presence
of and in the absence of 1 mM EDTA. In each case,
the measured Kis were unchanged relative to the stan-
dard assay buffer conditions.
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˚
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