title: Structure-activity relationship study of tricyclic necroptosis inhibitors.
abstract: Necroptosis is a regulated caspase-independent cell death mechanism that can be induced in multiple cell types and is characterized by morphological features resembling necrosis. Here we describe a series of tricyclic heterocycles (i.e., 3-phenyl-3,3a,4,5-tetrahydro-2H-benz[g]indazoles, 3-phenyl-2,3,3a,4-tetrahydro[1]benzopyrano[4,3-c]pyrazoles, 3-phenyl-2,3,3a,4-tetrahydro[1]benzothiopyrano[4,3-c]pyrazoles, and 5,5-dioxo-3-phenyl-2,3,3a,4-tetrahydro[1]benzothiopyrano[4,3-c]pyrazoles], collectively termed Nec-3, that can potently inhibit necroptosis. For example, compounds 8, 22, 41, 53, and 55 inhibit necroptosis in an FADD-deficient variant of human Jurkat T cells treated for 24 h with TNF-alpha with EC50 values in the range 0.15-0.29 microM. Distinct from the previously described series of hydantoin-containing indole derivatives (Nec-1), the Nec-3 series exhibits specificity in inhibiting TNF-alpha-induced necroptosis. A structure-activity relationship (SAR) study revealed that the (3R,3aR)-rel-diastereomers were more active than the (3R,3aS)-rel-diastereomers for all four ring systems. Introduction of fluorine or methoxy to the 8-position of the tricyclic ring and a methoxy to the 4-position of the pendent phenyl ring increased activity. Amides at the 2-position of the tricyclic ring were best. The Nec-3 series provides new tools for elucidating caspase-independent cell death pathways and potentially lead compounds for therapeutic development.
authors.affiliation: Laboratory for Drug Discovery in Neurodegeneration, Harvard Center for Neurodegeneration and Repair, Brigham & Women's Hospital and Harvard Medical School, 65 Landsdowne Street, Cambridge, Massachusetts 02139, USA.
authors.forename: Prakash G
authors.initials: PG
authors.lastname: Jagtap
authors.forename: Alexei
authors.initials: A
authors.lastname: Degterev
authors.forename: Sungwoon
authors.initials: S
authors.lastname: Choi
authors.forename: Heather
authors.initials: H
authors.lastname: Keys
authors.forename: Junying
authors.initials: J
authors.lastname: Yuan
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cuny
mesh_terms: D020169:Caspases / Q000502:physiology; D002460:Cell Line; D053200:Fas-Associated Death Domain Protein / Q000235:genetics; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009336:Necrosis; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D053200:Fas-Associated Death Domain Protein; D006575:Heterocyclic Compounds, 3-Ring; D007191:Indazoles; D011720:Pyrazoles; D014409:Tumor Necrosis Factor-alpha; D020169:Caspases