title: Diazinones as P2 replacements for pyrazole-based cathepsin S inhibitors.
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).
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA. mameriks@its.jnj.com
authors.forename: Michael K
authors.initials: MK
authors.lastname: Ameriks
authors.forename: Scott D
authors.initials: SD
authors.lastname: Bembenek
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Burdett
authors.forename: Ingrid C
authors.initials: IC
authors.lastname: Choong
authors.forename: James P
authors.initials: JP
authors.lastname: Edwards
authors.forename: Damara
authors.initials: D
authors.lastname: Gebauer
authors.forename: Yin
authors.initials: Y
authors.lastname: Gu
authors.forename: Lars
authors.initials: L
authors.lastname: Karlsson
authors.forename: Hans E
authors.initials: HE
authors.lastname: Purkey
authors.forename: Bart L
authors.initials: BL
authors.lastname: Staker
authors.forename: Siquan
authors.initials: S
authors.lastname: Sun
authors.forename: Robin L
authors.initials: RL
authors.lastname: Thurmond
authors.forename: Jian
authors.initials: J
authors.lastname: Zhu
mesh_terms: D002403:Cathepsins / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry*; D011720:Pyrazoles / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D011480:Protease Inhibitors; D011720:Pyrazoles; D002403:Cathepsins; C028217:cathepsin S