Structure-based design and pre-clinical characterization of selective and orally bioavailable Factor XIa inhibitors: Demonstrating the power of an integrated S1 protease family approach

The serine protease Factor XI (FXI) is a prominent drug target as it holds promise to deliver efficacious anti-coagulation without an enhanced risk of major bleeds. Several efforts have been described targeting the active form of the enzyme, FXIa. Herein we disclose our efforts to identify potent, selective, and orally bioavailable inhibitors of FXIa. Compound 1, identified from a diverse library of internal serine protease inhibitors, was originally designed as a complement Factor D inhibitor and exhibited sub-micromolar FXIa activity and an encouraging ADME profile while being devoid of peptidomimetic architecture. Optimization of interactions in the S1, S1β, and S1` pockets of FXIa through a combination of structure-based drug design and traditional medicinal chemistry led to the discovery of compound 23 with sub-nanomolar potency on FXIa, enhanced selectivity over other coagulation proteases, and a pre-clinical PK profile consistent with bid dosing in patients

Patient appropriateness for total knee arthroplasty and predicted probability of a good outcome

Objectives One-fifth of total knee arthroplasty (TKA) recipients experience a suboptimal outcome. Incorporation of patients’ preferences in TKA assessment may improve outcomes. We determined the discriminant ability of preoperative measures of TKA need, readiness/willingness and expectations for a good TKA outcome.Methods In patients with knee osteoarthritis (OA) undergoing primary TKA, we preoperatively assessed TKA need (Western Ontario-McMaster Universities OA Index (WOMAC) Pain Score and Knee injury and Osteoarthritis Outcome Score (KOOS) function, arthritis coping), health status, readiness (Patient Acceptable Symptom State, depressive symptoms), willingness (definitely yes—yes/no) and expectations (outcomes deemed ‘very important’). A good outcome was defined as symptom improvement (met Outcome Measures in Rheumatology and Osteoarthritis Research Society International (OMERACT–OARSI) responder criteria) and satisfaction with results 1 year post TKA. Using logistic regression, we assessed independent outcome predictors, model discrimination (area under the receiver operating characteristic curve, AUC) and the predicted probability of a good outcome for different need, readiness/willingness and expectations scenarios.Results Of 1,053 TKA recipients (mean age 66.9 years (SD 8.8); 58.6% women), 78.1% achieved a good outcome. With TKA need alone (WOMAC pain subscale, KOOS physical function short-form), model discrimination was good (AUC 0.67, 95% CI 0.63 to 0.71). Inclusion of readiness/willingness, depressive symptoms and expectations regarding kneeling, stair climbing, well-being and performing recreational activities improved discrimination (p=0.01; optimism corrected AUC 0.70, 0.66–0.74). The predicted probability of a good outcome ranged from 44.4% (33.9–55.5) to 92.4% (88.4–95.1) depending on level of TKA need, readiness/willingness, depressive symptoms and surgical expectations.Conclusions Although external validation is required, our findings suggest that incorporation of patients’ TKA readiness, willingness and expectations in TKA decision-making may improve the proportion of recipients that experience a good outcome