This publication describes uniform definitions for cardiovascular and stroke outcomes developed by the Standardized Data Collection for Cardiovascular Trials Initiative and the U.S. Food and Drug Administration (FDA). The FDA established the Standardized Data Collection for Cardiovascular Trials Initiative in 2009 to simplify the design and conduct of clinical trials intended to support marketing applications. The writing committee recognizes that these definitions may be used in other types of clinical trials and clinical care processes where appropriate. Use of these definitions at the FDA has enhanced the ability to aggregate data within and across medical product development programs, conduct meta-analyses to evaluate cardiovascular safety, integrate data from multiple trials, and compare effectiveness of drugs and devices. Further study is needed to determine whether prospective data collection using these common definitions improves the design, conduct, and interpretability of the results of clinical trials.

Modification of a series of pyrazole factor Xa inhibitors to incorporate an aminobenzisoxazole as the P(1) ligand resulted in compounds with improved selectivity for factor Xa relative to trypsin and plasma kallikrein. Further optimization of the P(4) moiety led to compounds with enhanced permeability and reduced protein binding. The SAR and pharmacokinetic profile of this series of compounds is described herein. These efforts culminated in 1-(3'-aminobenzisoxazol-5'-yl)-3-trifluoromethyl-N-[2-fluoro-4-[(2'-dimethylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide (11d), a potent, selective, and orally bioavailable inhibitor of factor Xa. On the basis of its excellent in vitro potency and selectivity profile, high free fraction in human plasma, good oral bioavailability, and in vivo efficacy in antithrombotic models, the HCl salt of this compound was selected for clinical development as razaxaban (DPC 906, BMS-561389).

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Studies are listed in order from top to bottom by percent of U.S. enrollment (shown in the column on right). Circles indicate the point estimate of the difference between log-hazard ratios (U.S. compared with non-U.S.), and arrows represent the 95% confidence interval for this difference.

Isoxazole derivatives R 0240Aminobenzisoxazoles with Biaryl P4 Moieties as Potent, Selective, and Orally Bioavailable Factor Xa Inhibitors.-Compound (X) shows the highest inhibitory activity and best bioavailability of all products tested. Compared with razaxaban, it reveals a sixfold enhancement in potency in the rabbit A-V shunt thrombosis model. -(QUAN*, M. L.; HAN, Q.; FEVIG, J. M.; LAM, P. Y. S.; BAI, S.; KNABB, R. M.; LUETTGEN, J. M.; WONG, P. C.; WEXLER, R. R.; Bioorg. Med. Chem. Lett. 16 (2006) 7, 1795-1798; Discovery Lab., Bristol-Myers Squibb Pharm. Res. Inst., Princeton, NJ 08543, USA; Eng.) -C. Oppel 28-125