The orally administered therapeutic captopril is widely used for treating hypertension, congestive heart failure, and cardiovascular disease. However, a number of undesirable side effects are associated with high doses of captopril. By coordinating a therapeutic to the upper (= beta) axial site of the naturally occurring macrocycle cobalamin (vitamin B-12), the absorption and cellular uptake of the therapeutic can be significantly enhanced. We report the synthesis of captopril-cobalamin, a derivative of vitamin B-12 in which captopril is bound via its thiol group at the beta-axial site of cobalamin. Characterization of captopril-cobalamin by H-1 NMR spectroscopy and X-ray diffraction shows that captopril-cobalamin exists in both solution and the solid state as a mixture of geometric isomers. Kinetic studies on the formation of captopril-cobalamin have been carded out, and the data fits a model in which the thiol form (RSH, k(1) = 40.9 +/-1.2 M-1 s(-1)) and the thiolate form of captopril (RS-, k(2) = 660 +/-170 M-1 s(-1)) react rapidly with aquacobalamin.