Effect of aminomethyl (N-mannich base) derivatization on the ability of S6-acetyloxymethyl-6-mercaptopurine prodrug to deliver 6-mercaptopurine through hairless mouse skin

A series of 9‐aminomethyl‐S6‐acetyloxymethyl‐6‐mercaptopurine (9‐AM‐6‐AOM‐6‐MP) prodrugs have been synthesized and characterized, and their ability to deliver total 6‐mercaptopurine (6‐MP) through hairless mouse skin has been measured. The 9‐AM‐6‐AOM‐6‐MP prodrugs are much more soluble in isopropyl myristate (IPM) than S6‐acetyloxymethyl‐6‐MP (6‐AOM‐6‐MP) itself or the corresponding 7‐aminomethyl‐6‐MP (7‐AM‐6‐MP) prodrugs. The 9‐AM‐6‐AOM‐6‐MP prodrugs were all more effective (1.8–4 times) than 6‐AOM‐6‐MP at delivering total 6‐MP, except for the piperidylmethyl derivative which only gave a comparable rate of delivery. The 9‐AM‐6‐AOM‐6‐MP prodrugs were also more effective (7–27 times) than the corresponding 7‐AM‐6‐MP prodrugs at delivering 6‐MP, except for the diethylaminomethyl derivative which only gave a comparable rate of delivery. In contrast to the 9‐aminomethyl‐S6‐pivaloyloxymethyl‐6‐MP (9‐AM‐6‐POM‐6‐MP) derivatives which generally delivered as much or more intact S6‐pivaloyloxymethyl‐6‐MP (6‐POM‐6‐MP) as 6‐MP, the 9‐AM‐6‐AOM‐6‐MP derivatives delivered mainly (80–95%) 6‐MP from IPM. There was a direct correlation between log experimental permeability coefficients for delivery of total 6‐MP (P∑) and the calculated solubility parameter values for the 9‐AM‐6‐AOM‐6‐MP prodrugs (δj), with the P∑ generally decreasing as the value of δj approached that of the vehicle, IPM. There was no significant effect of the prodrugs:IPM suspensions on the skin compared with 6‐MP:IPM suspension or IPM, as determined by a second application of a standard solute:vehicle complex.