Structure-Based Design and Preclinical 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 anticoagulation 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 submicromolar FXIa activity and an encouraging absorption, distribution, metabolism, and excretion (ADME) profile while being devoid of a peptidomimetic architecture. Optimization of interactions in the S1, S1ß, 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 subnanomolar potency on FXIa, enhanced selectivity over other coagulation proteases, and a preclinical pharmacokinetics (PK) profile consistent with bid dosing in patients.

Comparison of Knotless Barbed Suture Versus Monofilament Suture in the Oral Cavity of Cats.

The present study compares a knotless, barbed, absorbable suture material against a conventional monofilament absorbable suture material in oral mucosal wound closure. The parameters measured include time of closure and differences in healing at 2 and 4 weeks postoperatively. A prospective study comparing a knotless, barbed suture system with conventional absorbable sutures was undertaken in 19 cats. Nineteen cats had full mouth extractions performed. Following the extraction procedures, the incisions in the arcades (maxillary and mandibular) were apposed with the barbed, knotless suture system in a continuous pattern on one side and with a conventional smooth suture in an interrupted pattern on the other. Suturing times for each arcade were recorded. The material used to close the first side of each cat varied. Healing, dehiscence, and other complications were assessed at 2 and 4 weeks postoperatively. The average closure time (± standard deviation) per quadrant with conventional monofilament suture was 8.7 (±1.3) minutes, while barbed suture required an average of 5.1 (±1.1) minutes per quadrant to complete the suture. This difference (95% confidence interval) of 3.6 (±3.2-4.1) minutes per quadrant was statistically significant ( P < .001). Dehiscence and ranula-like swelling formation were noted as uncommon postoperative complications, but the differences were not significant between the groups. Barbed, knotless sutures resulted in faster closure times than conventional, simple interrupted, monofilament sutures with similar healing and complication rates. To the author's knowledge, there is no current literature comparing conventional absorbable monofilament sutures to a knotless, barbed, absorbable suture system for closure of oral mucosal incisions in cats.

Commissurorraphy in the Dog.

Commissurorraphy is a surgical procedure designed to move the lip commissure rostrally. This procedure may be helpful as a unilateral procedure in cases of unilateral mandibulectomy to support tongue function and improve esthetics. Bilateral commissurorraphy is utilized in cases of radical bilateral mandibulectomy and as a salvage procedure for support of bilateral mandibular fractures in cases where rigid surgical fixation is not feasible. Dehiscence is the most likely complication of commissurorraphy. Tension can be reduced at the rostral extent of the incision by utilizing mattress sutures, intravenous fluid tubing, and/or buttons to prevent tearing through sutures.

Small-molecule factor D inhibitors targeting the alternative complement pathway.

Complement is a key component of the innate immune system, recognizing pathogens and promoting their elimination. Complement component 3 (C3) is the central component of the system. Activation of C3 can be initiated by three distinct routes-the classical, the lectin and the alternative pathways-with the alternative pathway also acting as an amplification loop for the other two pathways. The protease factor D (FD) is essential for this amplification process, which, when dysregulated, predisposes individuals to diverse disorders including age-related macular degeneration and paroxysmal nocturnal hemoglobinuria (PNH). Here we describe the identification of potent and selective small-molecule inhibitors of FD. These inhibitors efficiently block alternative pathway (AP) activation and prevent both C3 deposition onto, and lysis of, PNH erythrocytes. Their oral administration inhibited lipopolysaccharide-induced AP activation in FD-humanized mice. These data demonstrate the feasibility of inhibiting the AP with small-molecule antagonists and support the development of FD inhibitors for the treatment of complement-mediated diseases.