New potent prolyl endopeptidase inhibitors: Synthesis and structure- activity relationships of indan and tetralin derivatives and their analogues

Article abstract of DOI:10.1021/jm00039a019

New compounds were synthesized by structural modification of 1-[1-(4- phenylbutanoyl)-L-prolyl]-pyrrolidine (SUAM-1221, 1) or 1-[1- (benzyloxycarbonyl)-L-prolyl]prolinal (Z-Pro-prolinal, 2) and were tested for in vitro inhibitory activities against purified prolyl endopeptidase (PEP) from canine brain. In a series of compounds which lack a formyl or a cyano group, 3-[3-[(S)-2-(1,2,3,4-tetrahydronaphthyl)acetyl]-L- thioprolyl]thiazolidine (13) exhibited an approximately 20-fold (IC₅₀ = 2.3 nM) increase in potency compared with 1. Compounds having a formyl or a cyano group showed much more potent inhibitory activities than those which lack such a functional group. Among all compounds tested in vitro, 1-[1-(2- indanylacetyl)-L-prolyl]prolinal (27), 1-[1-[(S)-2-(1,2,3,4- tetrahydronaphthyl)acetyl]-L-prolyl]prolinal (29), 1-[3-[(S)-2-(1,2,3,4- tetrahydronaphthyl)-acetyl]-L-thioprolyl]prolinal (30), (S)-2-cyano-1-[2- [(S)-2-(1,2,3,4-tetrahydronaphthyl)acetyl]-L-prolyl]pyrrolidine (34), and (S)-2-cyano-1-[3-[(S)-2-(1,2,3,4-tetrahydronaphthyl)acetyl]-L- thioprolyl]pyrrolidine (35) showed an approximately 2-fold (IC₅₀ ? 0.5 nM) increase in potency compared with 2. The structure-activity relationships of these compounds are discussed.