Initial Structure-Activity Relationships for a Caprolactam-based Series of Neutral Factor Xa Inhibitors: Lead Identification

Caprolactam urea 1, identified as a weak Factor Xa inhibitor screening hit (IC50 = 16 μM), served as the starting point for a limited parallel-synthesis driven SAR study to improve potency. Remarkably, the corresponding thiourea analog 8c (IC50 = 0.11 μM) was 145-fold more potent against Factor Xa compared to 1. In general, caprolactam analogs containing a thiourea linker were significantly more potent than their corresponding urea counterparts, and it is hypothesized that this is partly due to a conformational preference of the thiourea linkage which facilitates binding of the terminal groups of the inhibitors to the Factor Xa S1/S4 pockets. Analog 8c was selective against a panel of related serine proteases. Upon intra-duodenal administration in rats, 8c dose-dependently increased prothrombin time ex vivo, and when dosed i.v., it demonstrated efficacy in a rat model of venous thrombosis. This thiourea lead series formed the basis for follow-on investigations to discover potent drug-like Factor Xa inhibitors using the caprolactam scaffold but employing suitable thiourea surrogates.