Design, synthesis and biological evaluation of 6-chloro-quinolin-2-one derivatives as novel FXIa inhibitors.

A series of 6-chloro-quinolin-2-one derivatives were designed and synthesized as FXIa inhibitors by exploration of P1, P1 prime and P2 prime groups. Each compound was accessed for inhibitory effect on FXIa and some of them were evaluated in the clotting assay. 14c demonstrated excellent in-vitro potency (FXIa IC50: 15 nM, 2 x aPTT: 6.8 µM) and good in-vivo efficacy (prolonged in-vivo aPTT by more than 1-fold but not PT). Moreover, the pharmacokinetics property of 14c were evaluated following intravenous administration in rats, which indicated that 14c probably will be a clinical candidate for intravenous administration.

Umbilical artery Doppler indices in small for gestational age fetuses: correlation with adverse outcomes and placental abnormalities.

OBJECTIVE: The purpose of this study was to compare the screening efficiency of the umbilical artery systolic to diastolic ratio (S/D), pulsatility index (PI), and absent end-diastolic flow (AEDF) for adverse pregnancy outcomes and placental abnormalities in small for gestational age (SGA) fetuses. METHODS: We conducted a retrospective cohort study of Doppler examinations of 161 nonanomalous SGA fetuses. The reliability of the S/D and PI were quantified by intraclass correlation coefficients. The association of the S/D, PI, and AEDF with adverse outcomes and placental abnormalities was compared by the chi(2) test. RESULTS: There was a simple association of Doppler results with adverse outcomes, which was mitigated when controlled for gestational age. For all measures of adverse outcomes, the specificity of abnormal Doppler results exceeded the sensitivity, and the negative predictive value was greater than the positive predictive value. Comparing the S/D with the PI, there was no significant difference in the sensitivity; however, the specificity of the PI was at least 90% and exceeded that of the S/D for all outcomes. The intraclass correlation coefficients of the S/D and PI were similar, indicating no difference in reliability. Placental abnormalities were significantly more common in cases with abnormal Doppler values (positive predictive value, 94%) with no overlap in the types of placental lesions in most cases. CONCLUSIONS: As an initial screen for adverse outcomes in SGA fetuses, the umbilical artery Doppler S/D, PI, and AEDF were imprecise. However, these measures were all strongly and similarly predictive of placental abnormalities, especially lesions of maternal underperfusion and fetal vascular obstruction.