New potent prolyl endopeptidase inhibitors: synthesis and structure-activity relationships of indan and tetralin derivatives and their analogues.
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Tanaka Y, Niwa S, Nishioka H, Yamanaka T, Torizuka M, Yoshinaga K, Kobayashi N, Ikeda Y, Arai H
New potent prolyl endopeptidase inhibitors: synthesis and structure-activity relationships of indan and tetralin derivatives and their analogues.
J Med Chem. 1994 Jun 24;37(13):2071-8.
- PubMed ID
- 8027988 [ View in PubMed]
- Abstract
New compounds were synthesized by structural modification of 1-[1-(4-phenylbutanoyl)-L-prolyl]-pyrrolidine (SUAM-1221, 1) or 1-[1-(benzyloxycarbonyl)-L-proly]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]p rolinal (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 congruent to 0.5 nM) increase in potency compared with 2. The structure-activity relationships of these compounds are discussed.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Z-Pro-Prolinal Prolyl endopeptidase IC 50 (nM) 1.1 N/A N/A Details