Design, synthesis, and tripeptidyl peptidase II inhibitory activity of a novel series of (S)-2,3-dihydro-2-(4-alkyl-1H-imidazol-2-yl)-1H-indoles.

Butabindide, 1, was previously reported as a potent inhibitor (IC50 = 7 nM) of the serine protease enzyme tripeptidyl peptidase II (TPPII), an endogenous protease that degrades cholecystokinin-8 (CCK-8). We found that 1 has some inherent chemical instability, yielding diketopiperazine 2 fairly readily under mimicked physiological conditions. We therefore prepared imidazoles 3, which are void of 1's inherent instability, and have found that our novel analogues maintained comparable TPPII inhibitory activity (e.g.,for 3c, IC50 = 4 nM) as 1.