Individual symptom reduction and post-treatment severity: Varying levels of symptom amelioration in response to prolonged exposure for post-traumatic stress disorder.

Many patients evince significant post-traumatic stress disorder (PTSD) symptoms after a dose of an evidence-based treatment (EBT) for PTSD. Little research systematically addresses if individual PTSD symptoms are more or less resistant to change through an EBT for PTSD or have greater or lesser post-treatment severity levels. Two studies within VA medical centers provided data. Study 1 (n = 81) was drawn from a randomized clinical trial of Prolonged Exposure (PE), an EBT for PTSD. Study 2 (n = 225) was drawn from two PTSD specialty clinics employing PE. Symptoms were assessed pre- and post-treatments via semi-structured clinician interview (Study 1) and patient self-report (Studies 1 and 2). Most individual symptoms reduced about the same amount through the course of treatment except for avoidance, which showed greater reductions. High heterogeneity in post-treatment symptom severity was found with troubled sleep and hypervigilance displaying above average levels, and traumatic amnesia, foreshortened future, and flashbacks displaying below average levels. Method of symptom measurement had a modest impact on results, as semi-structured clinical interview results were moderately more differentiated than self-report measures. Results were generally consistent between an efficacy (i.e., extremely high, potentially artificial methodological control) and effectiveness (i.e., relatively more real world) context. Primary limitation is analysis of single items on semi-structured clinician interview and patient self-report scale when psychometric validation studies did not interpret measures this way. Moreover, DSM-IV criteria for PTSD were assessed. EBT augmentation and new treatment development should focus on further reducing both PTSD symptoms in general and on the specific symptoms of troubled sleep and hypervigilance, which persist to a greater degree. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Discovery and SAR of novel pyrazole-based thioethers as cathepsin S inhibitors. Part 2: Modification of P3, P4, and P5 regions.

A novel class of tetrahydropyrido-pyrazole thioether amines that display potency against human Cathepsin S have been previously reported. Here, further SAR investigations of the P3, P4, and P5 regions are described. In particular, 4-fluoropiperidine is identified as a competent P3 binding element when utilized in conjunction with a (S)-2-hydroxypropyl linker-containing P5 moiety and oxamide or sulfonamide P4 substitution.

Thioether acetamides as P3 binding elements for tetrahydropyrido-pyrazole cathepsin S inhibitors.

A series of tetrahydropyrido-pyrazole cathepsin S (CatS) inhibitors with thioether acetamide functional groups were prepared with the goal of improving upon the cellular activity of amidoethylthioethers. This Letter describes altered amide connectivity, in conjunction with changes to other binding elements, resulting in improved potency, as well as increased knowledge of the relationship between this chemotype and human CatS activity.

Discovery and SAR of novel pyrazole-based thioethers as cathepsin S inhibitors: part 1.

A series of pyrazole-based thioethers were prepared and found to be potent cathepsin S inhibitors. A crystal structure of 13 suggests that the thioether moiety may bind to the S3 pocket of the enzyme. Additional optimization led to the discovery of aminoethylthioethers with improved enzymatic activity and submicromolar cellular potency.

Cathepsin S inhibitors: 2004-2010.

INTRODUCTION: Cathepsin S, a lysosomal cysteine protease, plays an important role in antigen presentation. Its inhibition is expected to result in immunosuppression, making this enzyme an attractive target to potentially treat autoimmune and inflammatory diseases. AREAS COVERED: The focus of this review is on patent literature regarding small molecule inhibitors of cathepsin S published from 2004 to April 2010. Different structure classes based on binding strategies (covalent vs non-covalent) are surveyed and listed according to warhead type and research organization. EXPERT OPINION: Although > 40 patent applications have appeared between 2004 and 2010, the decrease in applications focusing on cathepsin S over the past 2 - 3 years may reflect a renewed interest in other cathepsins, especially cathepsin K, for which a small molecule inhibitor is currently in Phase III clinical trials.