Discovery of novel cathepsin S inhibitors by pharmacophore-based virtual high-throughput screening

The cysteine protease cathepsin S (CatS) is involved in the pathogenesis of autoimmune disorders, atherosclerosis, and obesity. Therefore, it represents a promising pharmacological target for drug development. We generated ligand-based and structure-based pharmacophore models for noncovalent and covalent CatS inhibitors to perform virtual high-throughput screening of chemical databases in order to discover novel scaffolds for CatS inhibitors. An in vitro evaluation of the resulting 15 structures revealed seven CatS inhibitors with kinetic constants in the low micromolar range. These compounds can be subjected to further chemical modifications to obtain drugs for the treatment of autoimmune disorders and atherosclerosis.

Cardiac rehabilitation uptake following myocardial infarction: cross-sectional study in primary care

Background Policies suggest that primary care should be more involved in delivering cardiac rehabilitation. However, there is a lack of information about what is known in primary care regarding patients' invitation or attendance. Aim To determine, within primary care, how many patients are invited to and attend rehabilitation after myocardial infarction (MI), examine sociodemographic factors related to invitation, and compare quality of life between those who do and do not attend. Design of study Review of primary care paper and computer records; cross-sectional questionnaire. Setting Northern Ireland general practices (38); stratified sample, based on practice size and health board area. Method Patients, identified from primary care records, 12-16?weeks after a confirmed diagnosis of MI, were posted questionnaires, including a validated MacNew post-MI quality-of-life questionnaire. Practices returned anonymised data for non-responders. Results Information about rehabilitation was available for 332 of the 432 patients identified (76.9%): 162 (37.5%) returned questionnaires. Of the total sample, 54.4% (235/432) were invited and 37.0% (160/432) attended; of those invited, 68.1% (160/235) attended. Invited patients were younger than those not invited (mean age 63?years [standard deviation SD 16] versus 68.5?years [SD 16]); mean difference 5.5?years (95% confidence interval [CI] = 1.7 to 9.3). Among questionnaire responders, those who attended were younger and reported better emotional, physical, and social functioning than non-attenders (P = 0.01; mean differences 0.44 (95% CI = 0.11 to 0.77), 0.48 (95% CI = 0.10 to 0.85) and 0.54 (95% CI = 0.15 to 0.94) respectively). Conclusion Innovative strategies are needed to improve cardiac rehabilitation uptake, integration of hospital and primary care services, and healthcare professionals' awareness of patients' potential for health gain after MI.