We have synthesized a series of 2-aminoethoxydiphenyl borate (2-APB, 2,2-diphenyl-1,3,2-oxazaborolidine) analogs and tested their ability to inhibit thrombin-induced Ca2+ influx in human platelets. The analogs were either synthesized by adding various substituents to the oxazaborolidine ring (methyl, dimethyl, tert-butyl, phenyl, methyl phenyl, and pyridyl) or increasing the size of the oxazaborolidine ring to seven- and nine-membered rings. NMR analysis of the boron-containing analogs suggests that each of them exist as a ring structure through the formation of an N -> B coordinate bond (except for the hexyl analog). The possibility that these boron-containing compounds formed dimers was also considered. All compounds dose-dependently inhibited thrombin-induced Ca2+ influx in human platelets, with the 2,2-diphenyl-1,3,2-oxazaborolidine5-one derivative having the weakest activity at 100 μM, whereas the (S)-4-benzyl and (R)-4-benzyl derivatives of 2-APB were approximately 10 times more potent than the parent 2-APB. Two nonboron analogs (3-methyl and 3-tert-butyl 2,2-diphenyl- 1,3-oxazolidine) were synthesized; they had approximately the same activity as 2-APB, and this implies that the presence of boron was not necessary for inhibitory activity. All of the compounds tested were also able to inhibit thrombin-induced calcium release. We concluded that extensive modifications of the oxazaborolidine ring in 2-APB can be made, and Ca2+-blocking activity was maintained.
Original Publication Citation
Dobrydneva, Y., Abelt, C. J., Dovel, B., Thadigiri, C. M., Williams, R. L., & Blackmore, P. F. (2006). 2-aminoethoxydiphenyl borate as a prototype drug for a group of structurally related calcium channel blockers in human platelets. Molecular Pharmacology, 69(1), 247-256. doi:10.1124/mol.105.015701
Dobrydneva, Yuliya; Abelt, Christopher J.; Dovel, Beth; Thadigiri, Celina M.; Williams, Roy L.; and Blackmore, Peter F., "2-Aminoethoxydiphenyl Borate as a Prototype Drug for a Group of Structurally Related Calcium Channel Blockers in Human Platelets" (2006). Chemistry & Biochemistry Faculty Publications. 133.