Damian O. Arnaiz

Design, synthesis, and in vitro biological activity of benzimidazole based factor Xa inhibitors

Inhibitors based on the benzimidazole scaffold showed subnanomolar potency against Factor Xa with 500-1000-fold selectivity against thrombin and 50-100-fold selectivity against trypsin. The 2-substituent on the benzimidazole ring had a strong impact on the FXa inhibitory activity. Crystallography studies suggest that the 2-substituent may have a conformational effect favoring the extended binding conformation.

Potent Triazolothione Inhibitor of Heat‐Shock Protein‐90

Heat‐shock protein‐90 is an attractive target for anticancer drugs, as heat‐shock protein‐90 blockers such as the ansamycin 17‐(allylamino)‐17‐demethoxygeldanamycin greatly reduce the expression of many signaling molecules that are disregulated in cancer cells and are key drivers of tumor growth and metastasis. While 17‐(allylamino)‐17‐demethoxygeldanamycin has shown promise in clinical trials, this compound class has significant template‐related drawbacks. In this paper, we describe a new, potent non‐ansamycin small‐molecule inhibitor of heat‐shock protein‐90, BX‐2819, containing resorcinol and triazolothione rings. Structural studies demonstrate binding of BX‐2819 to the ADP/ATP‐binding pocket of heat‐shock protein‐90. The compound blocked expression of heat‐shock protein‐90 client proteins in cancer cell lines and inhibited cell growth with a potency similar to 17‐(allylamino)‐17‐demethoxygeldanamycin. In a panel of four cancer cell lines, BX‐2819 blocked growth with an average IC50 value of 32 nm (range of 7–72 nm). Efficacy studies demonstrated that treatment with BX‐2819 significantly inhibited the growth of NCI‐N87 and HT‐29 tumors in nude mice, consistent with pharmacodynamic studies showing inhibition of heat‐shock protein‐90 client protein expression in tumors for greater than 16 h after dosing. These data support further studies to assess the potential of BX‐2819 and related analogs for the treatment of cancer.

Design, synthesis, and in vitro biological activity of indole-based factor Xa inhibitors

A series of indole and carbazole based inhibitors of factor Xa (FXa) has been investigated. The most potent compound inhibits FXa with a Ki of 0.2 nM and has 900- and 750-fold selectivity over thrombin and trypsin, respectively.