New potent prolyl endopeptidase inhibitors: synthesis and structure-activity relationships of indan and tetralin derivatives and their analogues.
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.
Tanaka
Y
Y
Central Research Laboratories, Zeria Pharmaceutical Company, Ltd., Saitama-ken, Japan.
Niwa
S
S
Nishioka
H
H
Yamanaka
T
T
Torizuka
M
M
Yoshinaga
K
K
Kobayashi
N
N
Ikeda
Y
Y
Arai
H
H
D000818:Animals; D001921:Brain / Q000201:enzymology; D004285:Dogs; D066298:In Vitro Techniques; D007189:Indans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D011392:Proline / Q000031:analogs & derivatives / Q000737:chemistry; D000085822:Prolyl Oligopeptidases; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D007189:Indans; D011758:Pyrroles; D015842:Serine Proteinase Inhibitors; D013764:Tetrahydronaphthalenes; C074327:N-(N-(phenyl)butyryl-L-prolyl)pyrrolidine; D011392:Proline; D012697:Serine Endopeptidases; D000085822:Prolyl Oligopeptidases; C046026:prolinal