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Figure 2. Active site of the model structure of compound 6i complexed
with cathepsin K. The cathepsin K carbons are colored magenta with
inhibitor 6i carbons colored green. The semi-transparent white surface
represents the molecular surface, while hydrogen bonds are depicted as
yellow dashed lines. This figure was generated using PYMOL version
12. Catalano, J. G.; Deaton, D. N.; Furfine, E. S.; Hassell, A.
M.; McFadyen, R. B.; Miller, A. B.; Miller, L. R.;
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New York, 1997; p 243.
64Gly, and 65Gly abuts the norleucine-derived P1 group
of the inhibitor, with one face of the n-butyl group form-
ing van der Waals interactions with the protease while
its terminal carbon is solvent exposed. Moreover, the
P2 lactam forms significant lipophilic interactions with
the S2 pocket composed of 67Tyr, 68Met, 134Ala,
163Ala, and 209Leu. These inhibitors do not contain a
P3 element that could potentially interact with the S3
subsite of cathepsin K. Incorporation of P3 groups
should enhance inhibitory activity at the cost of in-
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15. Many of the P2 moieties in these analogs contain a
stereogenic center adjacent to the carbamate. The epimers
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Kwhen modeled into the cathepsin Kactive site.
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In summary, this report showcases a structural screening
approach for lead generation. Starting from the keto-
amide cathepsin Kinhibitor 1, the P2 substituent was re-
placed with commercially available groups identified
through molecular modeling. This exercise produced
significant gains in inhibitory activity, including analogs
6f, 6g, and 6h, which were over 100-fold more potent
than the starting ketoamide. Modification of inhibitor
6h produced analog 6i, which was equipotent and 25%
orally bioavailable. Subsequent reports will detail efforts
to improve the properties of this series of pantolactone-
derived ketoamide-based cathepsin Kinhibitors.
17. Kopelevich, V. M.; Bulanova, L. N.; Gunar, V. I.
Tetrahedron Lett. 1979, 3893.
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Tomvaszek, T. A.; Tew, D.; Salyers, K.; Proksch, J.;
Ward, K.; Smith, B.; Levy, M.; Cummings, M. D.;
Haltiwanger, R. C.; Trescher, G.; Wang, B.; Hemling,
M. E.; Quinn, C. J.; Cheng, H. Y.; Lin, F.; Smith, W. W.;
Janson, C. A.; Zhao, B.; McQueney, M. S.; DꢁAlessio, K.;
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References and notes
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