Antithrombotic Effects of the Novel Small-Molecule Factor XIa Inhibitor Milvexian in a Rabbit Arteriovenous Shunt Model of Venous Thrombosis

Abstract Background Factor XIa (FXIa) is an emerging therapeutic target, and FXIa inhibition is a promising mechanism to improve therapeutic index over current anticoagulants. Milvexian (BMS-986177/JNJ-70033093) is an oral small-molecule FXIa inhibitor. Objective Milvexian's antithrombotic efficacy was characterized in a rabbit arteriovenous (AV) shunt model of venous thrombosis and compared with the factor Xa inhibitor apixaban and the direct thrombin inhibitor dabigatran. Methods The AV shunt model of thrombosis was conducted in anesthetized rabbits. Vehicle or drugs were administered as intravenous bolus plus a continuous infusion. Thrombus weight was the primary efficacy endpoint. Ex vivo activated partial thromboplastin time (aPTT), prothrombin time (PT), and thrombin time (TT) were measured as the pharmacodynamic responses. Results Milvexian dose dependently reduced thrombus weights by 34.3 ± 7.9, 51.6 ± 6.8 (p < 0.01; n = 5), and 66.9 ± 4.8% (p < 0.001; n = 6) versus vehicle at 0.25 + 0.17, 1.0 + 0.67, and 4.0 ± 2.68 mg/kg bolus + mg/kg/h infusion, respectively. Ex vivo clotting data supported a dose-dependent prolongation of aPTT (with 1.54-, 2.23-, and 3.12-fold increases from baseline upon the AV shunt start), but no changes in PT and TT. Dose-dependent inhibition in thrombus weight and clotting assays was also demonstrated for both apixaban and dabigatran as the references for the model validation. Conclusion Results demonstrate that milvexian is an effective anticoagulant for prevention of venous thrombosis in the rabbit model, which supports the utility of milvexian in venous thrombosis, as seen in the phase 2 clinical study

Modeling of precipitation of ultra-fine particles by pressure reduction over CO2-expanded liquids

A mathematical model has been developed to describe the process of precipitation of ultrafine particles by pressure reduction over gas (CO2)-expanded liquids. A rapid pressure reduction over a CO2-expanded organic solution, from 30–70 to 1 bar at 303 K decreases the solution temperature by 30–80 K in a very short span of time (0.5–1.5 min), which generates a rapid, high, and uniform supersaturation of the dissolved solute in the solution and facilitates precipitation of ultrafine particles. The model developed in this work estimates the supersaturation attained, nucleation and growth rates obtained during the pressure reduction over CO2-expanded organic solutions, and the particle size distribution of the precipitated particles. Cholesterol has been chosen as a model solute to be precipitated, and acetone has been chosen as a solvent. A new method has been developed for prediction of equilibrium solubility of solute which is affected by a decrease in CO2 mole fraction as well as a simultaneous decrease in solution temperature during pressure reduction. This method combines the semi-empirical approach of using the partial molar volume fraction of solvent in a CO2-solvent binary mixture and solid–liquid equilibrium data for a solute–solvent system. Size distributions of the precipitated particles have been calculated assuming primary nucleation (homogeneous as well as heterogeneous nucleation) and diffusion-limited growth kinetics. The predicted mean average particle sizes are then compared with the size of cholesterol particles precipitated by pressure reduction of a CO2-expanded acetone solution of cholesterol. The particle sizes predicted assuming heterogeneous nucleation are found to be closer to the experimentally observed particle sizes, indicating that the heterogeneous nucleation could be the main mechanism of nucleation, which could occur at the gas–liquid interface of the CO2 bubbling out of CO2-expanded solution during pressure reduction.by Rajarshi Chattaraj, Umesh Dhumal and Sameer V. Dalv

Himbacine-Derived Thrombin Receptor Antagonists: C₇‑Aminomethyl and C_9a-Hydroxy Analogues of Vorapaxar

We have synthesized several C₇-aminomethyl analogues of vorapaxar that are potent PAR-1 antagonists. Many of these analogues showed excellent in vitro binding affinity and pharmacokinetics profile in rats. Compound <b>6a</b> from this series showed excellent PAR-1 activity (<i>K</i>_i = 5 nM). We have also synthesized a C_9a-hydroxy analogue of vorapaxar, which showed very good PAR-1 affinity (<i>K</i>_i = 19.5 nM) along with excellent rat pharmacokinetic profile and ex vivo efficacy in the cynomolgus monkey

Himbacine-Derived Thrombin Receptor Antagonists: C₇‑Spirocyclic Analogues of Vorapaxar

We have synthesized several C₇-spirocyclic analogues of vorapaxar and evaluated their in vitro activities against PAR-1 receptor. Some of these analogues showed activities and rat plasma levels comparable to vorapaxar. Compound <b>5c</b> from this series showed excellent PAR-1 activity (<i>K</i>_i = 5.1 nM). We also present a model of these spirocyclic compounds docked to the PAR-1 receptor based on the X-ray crystal structure of vorapaxar bound to PAR-1 receptor. This model explains some of the structure–activity relationships in this series