化合物信息

Description

Cardiovascular Disease

Description

BMS-740808 is a highly potent, selective inhibitor of blood coagulation factor Xa (fXa) with K_i with 0.03 nM.

Targets

IC₅₀

In Vitro

BMS-740808 is highly potent with a rapid onset of inhibition (2.7 × 10⁷ M^-1 s^-1), selective (>1000-fold over other proteases), efficacious in the AVShunt thrombosis model. BMS-740808 is synthesized by modification of employing bicyclic pyrazolo-pyridinone scaffold to Razaxaban, a pyrazole based fXa inhibitor. Especially for BMS-740808, the introduction of a 3(R)-hydroxyl moiety on the pyrrolidine ring results in a significant enhancement in potency. BMS-740808 also shows the high affinity for thrombin. ^[1]

In Vivo

The pharmacokinetic profile for BMS-740808 is comparable to that of Razaxaban with moderate half life, whereas BMS-740808 shows low clearance, low V_dss, moderate half life and high oral bio-availability, which is quite possibly due to the hydroxyl substituent on the cyclic amino moiety. ^[1]

Clinical Trials

Features

Ki Determination

FXa (1 nM) is added to a 96-well plate containing BMS-740808 (5 pM to 3 μM) in buffer A (20 mM HEPES, 0.15 M NaCl, 0.1% PEG-8000, 5 mM CaCl₂, pH 7.4). S-2765 (N-α-Z-d-Arg-Gly-Arg-p Nitroanilide) at 200 μM is added, and substrate hydrolysis is monitored at 405 nm. Data are analyzed by Batch K_i software.

Animal Models

Male rabbit AVShunt thrombosis model.

Formulation

BMS-740808 is dissolved in saline.

Doses

2 μM

Administration

Given as continuous i.v. infusion via the jugular vein