IN-VIVO ACTIVITY OF RETINOID ESTERS IN SKIN IS RELATED TO IN-VITRO HYDROLYSIS RATE

BMS-181163 (4-acetamidophenyl retinoate, previously reported as BMY-30123), the acetamidophenyl ester of all-trans-retinoic acid (tRA), is topically active in various retinoid-sensitive animal models, but was recently shown to be ineffective for the treatment of acne in patients. To determine whether BMS-181163 functions as a prodrug of tRA in mice but not in man, the relative rates of ester hydrolysis in mouse and human skin homogenates were determined. In-vitro hydrolysis assays showed that BMS-181163 was substantially hydrolysed in mouse skin homogenates and minimally in human skin preparations. In addition, a series of phenyl esters of tRA and several known active synthetic retinoids (Ch-80: (E)-4-[3-oxo-3-(5,6,7,8-tetrahydro-5,5,8-tetra methyl-2-naphthalenyl)-1-propenyl] benzoic acid; CD-271: 6-[3-(1-adamantyl)-4-methyoxyphenyl]-2-naphthoic acid; and TTNPB: (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl]-1-propenyl]benzoic acid) was prepared and hydrolysis rates and in-vivo (rhino mouse utriculi reduction) activities were compared. The hydrolysis rates of the six test retinoid phenyl esters, ranging from 0.06 to 2.0h(-1), were found to correlate with the in-vivo activity. Those esters (BMS-181163 and acetamidophenyl esters of Ch-80 and TTNPB) with a higher hydrolysis rate exhibited in-vivo activity only slightly lower than their parent free acid retinoids. In contrast, the three phenyl esters with a hydrolysis rate less than 0.3 h(-1) were inactive in-vivo. Data from both approaches suggest that the breakdown of the phenyl ester linkage in this series is essential for the respective in-vivo activity and that the active phenyl esters of retinoids function as prodrugs.