title: 2-aminoethoxydiphenyl borate as a prototype drug for a group of structurally related calcium channel blockers in human platelets.
abstract: 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 Ca(2+) 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 Ca(2+) influx in human platelets, with the 2,2-diphenyl-1,3,2-oxazaborolidine-5-one derivative having the weakest activity at 100 microM, 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 Ca(2+)-blocking activity was maintained.
authors.affiliation: Department of Physiological Sciences, Eastern Virginia Medical School, P.O. Box 1980, Norfolk, VA 23501, USA.
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Dobrydneva
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Abelt
authors.forename: Beth
authors.initials: B
authors.lastname: Dovel
authors.forename: Celina M
authors.initials: CM
authors.lastname: Thadigiri
authors.forename: Roy L
authors.initials: RL
authors.lastname: Williams
authors.forename: Peter F
authors.initials: PF
authors.lastname: Blackmore
mesh_terms: D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D001896:Boron Compounds / Q000737:chemistry / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D017136:Ion Transport; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D013917:Thrombin / Q000494:pharmacology
chemical_list: D001896:Boron Compounds; D002121:Calcium Channel Blockers; C109986:2-aminoethoxydiphenyl borate; D013917:Thrombin; D002118:Calcium