Qun Dang, K. Raja Reddy, Srinivas Rao Kasibthatla, Tao Jiang, Frank Taplin, Tony Gibson, Scott C. Potter6, Paul D. van Poelje, M. Rami Reddy and Mark D. Erion
To discover an alternative series of fructose 1,6-bisphosphatase (FBPase) inhibitors that is suitable for oral delivery via prodrugs, the 4-amino group was removed from the initial 4-aminobenzimidazole lead series, since the number of hydrogen bond donors has been suggested to affect oral bioavailability (OBAV). Several desaminobenzimidazoles were discovered as potent inhibitors of FBPase. Compound 2.8 inhibits both human and rat liver FBPase with IC 50 ’s of 0.2 and 2 μ M, respectively. Using compound 2.8 as a tool compound, various prodrugs were explored with several cyclic ester prodrugs showing >10% OBAV. The more than 5-fold improvement of OBAV indicates that removal of the 4-amino group from the 4-aminobenzimidazole scaffold renders the scaffold more suitable for oral delivery via prodrugs. Moreover, OBAV SAR suggests that both molecular weight and lipophilicity (judging by cLogP) are important factors to consider when optimizing for OBAV. ©2000 Elsevier Science Ltd. All rights reserved.