New Potent Prolyl Endopeptidase Inhibitors: Synthesis and Structure-Activity Relationships of Indan and Tetralin Derivatives and Their Analogs
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....
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Veröffentlicht in: | Journal of medicinal chemistry 1994-06, Vol.37 (13), p.2071-2078 |
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Sprache: | eng |
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Zusammenfassung: | 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. |
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ISSN: | 0022-2623 1520-4804 |
DOI: | 10.1021/jm00039a019 |