Diazinones as P2 replacements for pyrazole-based cathepsin S inhibitors

doi:10.1016/j.bmcl.2010.05.086

Bioorganic & Medicinal Chemistry Letters

Volume 20, Issue 14, 15 July 2010, Pages 4060-4064

https://doi.org/10.1016/j.bmcl.2010.05.086 Get rights and content

Abstract

A pyridazin-4-one fragment 4 (hCatS IC₅₀ = 170 μM) discovered through Tethering was modeled into cathepsin S and predicted to overlap in S2 with the tetrahydropyridinepyrazole core of a previously disclosed series of CatS inhibitors. This fragment served as a template to design pyridazin-3-one 12 (hCatS IC₅₀ = 430 nM), which also incorporates P3 and P5 binding elements. A crystal structure of 12 bound to Cys25Ser CatS led to the synthesis of the potent diazinone isomers 22 (hCatS IC₅₀ = 60 nM) and 27 (hCatS IC₅₀ = 40 nM).

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References and notes (20)

R.E. Burden et al.
Clin. Cancer Res.
(2009)
S. Taleb et al.
Clin. Chem. Lab. Med.
(2007)
E. Lutgens et al.
Circulation
(2005)
W. Wendt et al.
Brain Res.
(2008)
O. Irie et al.
J. Med. Chem.
(2008)
M. Congreve et al.
J. Med. Chem.
(2008)
(b)Jahnke, W., Erlanson, D. A., Eds. Fragment-Based Approaches in Drug Discovery. In Methods and Principles in...
Y. Gong et al.
Heterocycles
(2004)
R. Roberts
Drug News Perspect.
(2005)
S. Gupta et al.
Exp. Opin. Ther. Targets
(2008)
W. Liu et al.
Drug News Perspect.
(2004)
T.Y. Nakagawa et al.
Immunity
(1999)
R.L. Thurmond et al.
J. Med. Chem.
(2004)
R.L. Thurmond et al.
J. Pharmacol. Exp. Ther.
(2004)
D.J. Gustin et al.
Bioorg. Med. Chem. Lett.
(2005)
(a)Allen, D.; Ameriks, M. K.; Axe, F. U.; Burdett, M.; Cai, H.; Choong, I.; Edwards, James P.; Lew, W.; Meduna, S. P....(b)Allen, D.; Ameriks, M. K.; Axe, F. U.; Burdett, M.; Cai, H.; Choong, I.; Edwards, J. P.; Lew, W.; Meduna, S. P. PCT...

There are more references available in the full text version of this article.

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^†: Former employee of Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

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Diazinones as P2 replacements for pyrazole-based cathepsin S inhibitors

Abstract

Graphical abstract

Clin. Cancer Res.

Clin. Chem. Lab. Med.

Circulation

Brain Res.

J. Med. Chem.

J. Med. Chem.

Heterocycles

Drug News Perspect.

Exp. Opin. Ther. Targets

Drug News Perspect.

Immunity

J. Med. Chem.

J. Pharmacol. Exp. Ther.

Bioorg. Med. Chem. Lett.