We next replaced the ester group as the second set of analogues, which may be labile, by an amide (Scheme 4) using glycine or β-alanine as building blocks. The synthesis began with an amide coupling between a Boc-protected glycine (n=1) or β-alanine (n=2) and 2-amino-5-chlorobenzophenone to afford intermediate XZ-4a/b (Scheme 4). Following the removal of the Boc protecting group was achieved quantitatively using HCl (4 M) in dioxane yielding compounds XZ-5a/b. The hydrochloride salts XZ-5a/b were then coupled with 2-methoxycinnamic acid to give the desired products XZ-6a/b (Scheme 4). The third set of analogues contains modifications of the ketone moiety in the original molecule to an amide. The synthesis began with a DCC-catalyzed coupling between methyl 2-amino-5-chlorobenzoate and acetoxyacetic acid to give intermediate XZ-7 (Scheme 5). The acetyl group was then removed with potassium carbonate in methanol to provide alcohol XZ-8, which was then transformed into intermediate XZ-9 via a Steglich esterification reaction. The last step involved a selective cleavage of the methyl ester using lithium iodide followed by an amide coupling to afford the desired product XZ-10. Biological evaluation revealed that the ester substitution for an amide is beneficial for the potency (XZ-3a vs. XZ-6a (Table ). This change led to a structure closer to the Gly present in the natural substrate. As a result, the amide is forming an additional interaction with the binding site. Other changes did not substantially improve the potency. Based on the docking study, we believe that changes on the right portion of the molecule combined with this amide change will lead to improved potencies.