ABSTRACT
OBJECTIVE. The purpose of this study was to evaluate the variation of the posterior radioscaphoid (RS) angle in patients with and without scapholunate ligament (SLL) tears during wrist radioulnar deviation. SUBJECTS AND METHODS. Seventy-three patients with clinically suspected scapholunate instability were prospectively evaluated with 4D CT and CT arthrography from February 2015 to April 2018. The posterior RS angle is formed between the articular surface of the scaphoid fossa of the radius and the most posterior point of the scaphoid in the sagittal plane. Two independent radiologists calculated this angle during radioulnar deviation. Posterior RS angles were correlated with the SLL status and the presence of a scapholunate diastasis on conventional stress radiographs. RESULTS. Readers 1 and 2 found mean posterior RS angles of 99° and 98°, respectively, in patients without and 107° and 111°, respectively, in patients with a scapholunate diastasis. The posterior RS angle amplitude varied 7.6-9.3° in the subgroups studied. The reproducibility of posterior RS angle measurement was considered good (intraclass correlation coefficient, 0.73). Mean posterior RS angles increased 6-10% and 12-14% when patients with an intact SLL were compared with those with partial tears and full tears, respectively (p < 0.001). These values also increased 8-13% when patients with diastasis were compared with those without (p < 0.0001). A dynamic acquisition was not necessary to assess this angle, with neutral posterior RS angles yielding a sensitivity of 64% and 72% and specificity of 79% and 94% for the diagnosis of SLL tears by readers 1 and 2, respectively. CONCLUSION. Posterior RS angle tended to increase with the severity of SLL tears and with the presence of scapholunate instability and yielded high sensitivity and specificity for the detection of SLL tears.
Subject(s)
Carpal Joints/diagnostic imaging , Four-Dimensional Computed Tomography , Joint Dislocations/diagnostic imaging , Ligaments, Articular/diagnostic imaging , Ligaments, Articular/injuries , Scaphoid Bone/diagnostic imaging , Adolescent , Adult , Aged , Arthrography , Female , Humans , Lunate Bone , Male , Middle Aged , Reproducibility of Results , Rupture , Sensitivity and Specificity , Young AdultABSTRACT
Rhodesain (RD) is a parasitic, human cathepsin L (hCatL) like cysteine protease produced by Trypanosoma brucei ( T. b.) species and a potential drug target for the treatment of human African trypanosomiasis (HAT). A library of hCatL inhibitors was screened, and macrocyclic lactams were identified as potent RD inhibitors ( Ki < 10 nM), preventing the cell-growth of Trypanosoma brucei rhodesiense (IC50 < 400 nM). SARs addressing the S2 and S3 pockets of RD were established. Three cocrystal structures with RD revealed a noncovalent binding mode of this ligand class due to oxidation of the catalytic Cys25 to a sulfenic acid (Cys-SOH) during crystallization. The P-glycoprotein efflux ratio was measured and the in vivo brain penetration in rats determined. When tested in vivo in acute HAT model, the compounds permitted up to 16.25 (vs 13.0 for untreated controls) mean days of survival.
Subject(s)
Cathepsin L/antagonists & inhibitors , Cysteine Endopeptidases/metabolism , Cysteine Proteinase Inhibitors/pharmacology , Lactams, Macrocyclic/pharmacology , Trypanocidal Agents/pharmacology , Trypanosoma brucei rhodesiense/drug effects , Animals , Binding Sites , Blood-Brain Barrier/metabolism , Cell Line , Cysteine Endopeptidases/chemistry , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/chemistry , Cysteine Proteinase Inhibitors/pharmacokinetics , Drug Repositioning , Humans , Lactams, Macrocyclic/chemical synthesis , Lactams, Macrocyclic/chemistry , Lactams, Macrocyclic/pharmacokinetics , Ligands , Male , Mice, Inbred C57BL , Molecular Structure , Rats , Structure-Activity Relationship , Swine , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacokineticsABSTRACT
We describe the design, using shape comparison and fast docking computer algorithms, and rapid parallel synthesis of a 1300 member array based on GSK7721, a 4-aminobenzonitrile androgen receptor (AR) antagonist identified by focused screening of the GSK compound collection. The array yielded 352 submicromolar and 17 subnanomolar AR agonists as measured by a cell-based reporter gene functional assay. The rapid synthesis of a large number of active compounds provided valuable information in the optimization of AR modulators, which may be useful in treating androgen deficiency in aging males.
Subject(s)
Androgen Receptor Antagonists , Combinatorial Chemistry Techniques/methods , Nitriles/chemical synthesis , Nitriles/pharmacology , Algorithms , Androgens , Animals , Cell Line , Drug Design , Haplorhini , Magnetic Resonance Spectroscopy , Nitriles/chemistry , Spectrometry, Mass, Fast Atom Bombardment , Structure-Activity RelationshipABSTRACT
Traditional approaches to discovery of selective estrogen receptor modulators (SERMs) have relied on ER binding and cell-based estrogen response element-driven assays to identify compounds that are osteoprotective but nonproliferative in breast and uterine tissues. To discover new classes of potential SERMs, we have employed a cell-free microsphere-based binding assay to rapidly characterize ERalpha interactions with conformation-sensing cofactor or phage display peptides. Peptide profiles of constrained triarenes were compared to known proliferative and nonproliferative ER ligands to discover potent quinoline-based ligands with minimal Ishikawa cell stimulation.
