title: Optimization of tricyclic Nec-3 necroptosis inhibitors for in vitro liver microsomal stability.
abstract: Necroptosis is a regulated caspase-independent cell death pathway with morphological features resembling passive non-regulated necrosis. Several diverse structure classes of necroptosis inhibitors have been reported to date, including a series of 3,3a,4,5-tetrahydro-2H-benz[g]indazoles (referred to as the Nec-3 series) displaying potent activity in cellular assays. However, evaluation of the tricyclic necroptosis inhibitor's stability in mouse liver microsomes indicated that they were rapidly degraded. A structure-activity relationship (SAR) study of this compound series revealed that increased liver microsomal stability could be accomplished by modification of the pendent phenyl ring and by introduction of a hydrophilic substituent (i.e., α-hydroxyl) to the acetamide at the 2-position of the tricyclic ring without significantly compromising necroptosis inhibitory activity. Further increases in microsomal stability could be achieved by utilizing the 5,5-dioxo-3-phenyl-2,3,3a,4-tetrahydro-[1]benzothiopyrano[4,3-c]pyrazoles. However, in this case necroptosis inhibitory activity was not maintained. Overall, these results provide a strategy for generating potent and metabolically stable tricyclic necrostatin analogs (e.g., 33, LDN-193191) potentially suitable for in vivo studies.
authors: Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham & Women's Hospital and Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139, USA.
authors: Sungwoon
authors: S
authors: Choi
authors: Heather
authors: H
authors: Keys
authors: Richard J
authors: RJ
authors: Staples
authors: Junying
authors: J
authors: Yuan
authors: Alexei
authors: A
authors: Degterev
authors: Gregory D
authors: GD
authors: Cuny
mesh_terms: D000818:Animals; D004355:Drug Stability; D006801:Humans; D007191:Indazoles / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D019169:Jurkat Cells; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D008958:Models, Molecular; D009336:Necrosis / Q000188:drug therapy*; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D007191:Indazoles; D011720:Pyrazoles