Sex-related differences in QTc effects potential of drugs.

The objective of this study was to examine the drug-induced sex differences in corrected QT (QTc) interval by re-analyzing the data collected in thorough QT studies submitted to the US Food and Drug Administration (FDA). We examined 64 studies available in the FDA database by performing a time-matched, baseline adjusted ANCOVA on the QTc response stratified by sex. We used several summaries to capture the differences between males and females in drug response QTc effects. They included sample means, upper confidence intervals, and areas under the curves. At baseline, females tend to have a higher QTc response than males. After treatment, various summaries suggest that females tend to have a higher QTc effect than males. However, the magnitude of the difference is small and is often not statistically significant. Several limitations can be raised about these available data: 1) available QT studies were not designed to examine the sex differences in QTc effects, 2) the findings were undermined by large variations seen in QT data, and 3) our summary statistics are descriptive in nature and are not for inferential purposes. Nonetheless, the results suggest that females tend to have a higher QTc effect than males, although the difference tends to be small. Further research is needed to formally address the question.

Aminobenzisoxazoles with biaryl P4 moieties as potent, selective, and orally bioavailable factor Xa inhibitors.

We have previously reported on a series of aminobenzisoxazoles as potent, selective, and orally bioavailable factor Xa inhibitors, which culminated in the discovery of razaxaban. Herein, we describe another approach to improve factor Xa inhibitory potency and pharmacokinetic profile by incorporating basic and water soluble functionalities on the terminal ring of the P4 biaryl group found in our earlier Xa inhibitors. This approach resulted in a series of potent, selective, and orally bioavailable factor Xa inhibitors.

Discovery of 1-(3'-aminobenzisoxazol-5'-yl)-3-trifluoromethyl-N-[2-fluoro-4- [(2'-dimethylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide hydrochloride (razaxaban), a highly potent, selective, and orally bioavailable factor Xa inhibitor.

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).