Download MendeleyDiazinones as P2 replacements for pyrazole-based cathepsin S inhibitors
Ameriks, M.K., Bembenek, S.D., Burdett, M.T., Choong, I.C., Edwards, J.P., Gebauer, D., Gu, Y., Karlsson, L., Purkey, H.E., Staker, B.L., Sun, S., Thurmond, R.L., Zhu, J.(2010) Bioorg Med Chem Lett 20: 4060-4064
- PubMed: 20541404
- DOI: https://doi.org/10.1016/j.bmcl.2010.05.086
- Primary Citation of Related Structures:
5QBV, 5QBY - PubMed Abstract:
A pyridazin-4-one fragment 4 (hCatS IC(50)=170 microM) 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 IC(50)=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 IC(50)=60 nM) and 27 (hCatS IC(50)=40 nM).
Organizational Affiliation:
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA. mameriks@its.jnj.com
