ABSTRACT
Leucine-rich repeat kinase 2 (LRRK2) has been suggested as a potential therapeutic target for Parkinson's disease. Herein we report the discovery of 5-substituent-N-arylbenzamide derivatives as novel LRRK2 inhibitors. Extensive SAR study led to the discovery of compounds 8e, which demonstrated potent LRRK2 inhibition activity, high selectivity across the kinome, good brain exposure, and high oral bioavailability.
Subject(s)
Benzamides/pharmacology , Drug Discovery , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Administration, Oral , Benzamides/administration & dosage , Benzamides/chemistry , Dose-Response Relationship, Drug , Humans , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism , Molecular Structure , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
Assault of staff in psychiatric hospitals is a frequent occurrence, and studies indicate that hospital staff are at risk of developing post-traumatic stress disorder (PTSD). We performed a correlational study with a convenience sample of 172 staff in a psychiatric hospital and compared the rate of traumatic events (TEs), resilience, confidence, and compassion fatigue to PTSD symptoms (PTSS). Regression analyses identified two variables that were unique predictors of PTSS: (1) trauma-informed care (TIC) meeting attendance and (2) burnout symptoms. Severe TEs, age, and compassion satisfaction also contributed to the model. Attention to these factors may help reduce PTSS in psychiatric staff.
Subject(s)
Compassion Fatigue/epidemiology , Hospitals, Psychiatric , Nursing Staff, Hospital/psychology , Psychiatric Nursing , Stress Disorders, Post-Traumatic/epidemiology , Adult , Burnout, Professional , Female , Humans , Male , Middle Aged , Resilience, Psychological , Self Concept , Young AdultABSTRACT
Leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for some forms of Parkinson's disease. Here we report the discovery and characterization of 2-arylmethyloxy-5-subtitutent-N-arylbenzamides with potent LRRK2 activities exemplified by GSK2578215A which exhibits biochemical IC(50)s of around 10 nM against both wild-type LRRK2 and the G2019S mutant. GSK2578215A exhibits exceptionally high selectivity for LRRK2 across the kinome, substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentration of 0.3-1.0 µM in cells and in mouse spleen and kidney, but not in brain, following intraperitoneal injection of 100mg/kg.
Subject(s)
Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , 3T3 Cells , Animals , Brain/metabolism , Cell Line , Drug Discovery , HEK293 Cells , Humans , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 , Male , Mice , Models, Molecular , Mutation , Parkinson Disease/drug therapy , Parkinson Disease/enzymology , Parkinson Disease/genetics , Protein Kinase Inhibitors/pharmacokinetics , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Structural Homology, ProteinABSTRACT
Twenty two analogues of SB-203207 have been prepared by total synthesis, and evaluated as inhibitors of a range of tRNA synthetases. Changes to the bicyclic core, removing either the terminal amino substituent or the sulfonyl group from the side chain, and altering either the carbon skeleton or stereochemistry of the isoleucine residue, decreases the potency of inhibition of isoleucyl tRNA synthetase. Substituting the isoleucine residue with other amino acids produces inhibitors of the corresponding synthetases. In particular, a methionine derivative is 50-100 times more potent against methionyl tRNA synthetase than against any of the corresponding isoleucyl, leucyl, valyl, alanyl and prolyl synthetases.
Subject(s)
Indenes/chemical synthesis , Indenes/pharmacology , Isoleucine-tRNA Ligase/antagonists & inhibitors , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Amino Acids/chemistry , Amino Acyl-tRNA Synthetases , Animals , Inhibitory Concentration 50 , Liver/enzymology , Rats , Staphylococcus aureus/enzymology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The antimicrobial natural product chuangxinmycin has been found to be a potent and selective inhibitor of bacterial tryptophanyl tRNA synthetase (WRS). A number of analogues have been synthesised. The interaction with WRS appears to be highly constrained, as only sterically smaller analogues afforded significant inhibition. The only analogue to show inhibition comparable to chuangxinmycin also had antibacterial activity. WRS inhibition may contribute to the antibacterial action of chuangxinmycin.