Initial Structure-Activity Relationships for a Caprolactam-based Series of Neutral Factor Xa Inhibitors: Lead Identification
Gregory S. Bisacchi,
Philip D. Stein,
Jack Z. Gougoutas,
Karen S. Hartl,
R. Michael Lawrence,
William A. Schumacher,
Thomas E. Steinbacher,
Steven M. Seiler.
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.
Keywords: Factor Xa, FXa inhibitor, caprolactam, serine protease
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