Tamoxifen and its analogs as calcium channel modulators in platelets: SAR study of triphenylethylene compounds

Anti‐breast cancer drug tamoxifen and its metabolite 4‐hydroxytamoxifen (4OHTam) are non‐steroidal analogs of estradiol. While studying non‐genomic effects of steroids, we found that tamoxifen and 4OHTam promote calcium influx into human platelets, leading to platelet activation and increasing risk of thrombosis. To determine pharmacophore responsible for calcium influx, SAR studies were performed on the set of newly synthesized triphenylethylene analogs of tamoxifen. Fura‐2 was used to monitor calcium influx in human platelets. Cell‐impermeable derivatives of 4OHTam promote calcium influx into platelets, thus indicating membrane site of action. Activity of these compounds depends on the linker length. Triphenylethylene derivatives, which are devoid of amino ethanol moiety, switched their action from agonists of calcium entry to antagonists. Triphenylethylene compounds block, not activate thrombin‐ and tamoxifen induced calcium influx. Structurally triphenylethylenes resemble DES (diethylstilbestrol), the most potent inhibitor of CRAC and SOCC. Therefore, triphenylethylenes are transitional structures from calcium agonist (tamoxifen and 4OHTam) to calcium antagonist (DES), though they all share the same stilbene pharmacophore. SAR shows how simple structural modifications can lead to a complete shift in the pharmacological activity among structurally related compounds. (Supported by grants from CHRB of Virginia and Cancer Research and Prevention Foundation to YD and Army Breast Cancer Research Program to RW).