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Design and Synthesis of Icariin Analogues as a PDE-5 inhibitors
Erectile dysfunction (ED) is a sexual disorder mainly caused by decrease in cellular concentration of cyclic guanosine monophosphate (cGMP). Phosphodiesterase type-5 (PDE-5), predominantly responsible for degradation of cGMP, has been considered a potential therapeutic target for ED. Inhibitors such as sildenafil (Viagra®), tadalafil (Cialis®) and vardenafil (Levitra®) protect cGMP from degradation by cGMP-specific esterase, PDE-5 in the corpus cavernosum . However, several adverse drug reactions (ADRs) with PDE5 inhibitors are reported including priapism and visual disturbances, mainly caused by cross-inhibition with PDE-6. Recent studies by Dell'Agli et al. have shown that icariin (C33H40O15), a flavonol glycoside and major constituent of Yin Yang Huo (horny goat weed, Herba epimedii), is able to relax cavernous smooth muscle and enhance erectile function. In vitro study revealed that the icariin showed an IC50 value of 5.9mM and simple modification of both glycoside moieties yielded an IC50 75 nM against PDE-5 with a PDE-5/PDE-6 selectivity ratio greater than that of sildenafil. To identify potent selective PDE-5 inhibitors, virtual screening of natural product databases including in-house database, de novo design, synthesis and structure activity relationships of icariin were undertaken.
Acknowledgements: This research is supported in part by Science Based Authentication of Dietary Supplements and Botanical Dietary Supplement Research funded by the Food and Drug Administration grant numbers 5U01FD002071–10 and 1U01FD003871–02.
References:  Corbin JD, Francis SH (2002) Int J Clin Pract, 56: 453–459.  Dell'Agli M, Galli GV, et al. (2008)J Nat Prod 71: 1513–1517.