Structure activity relationship of inhibitors specific for prolyl endopeptidase.
Structural requirements of N-blocked L-proline derivatives as specific inhibitors for prolyl endopeptidase were investigated using a series of substrate analogs. Replacement of L-proline by its D-isomer remarkably reduced the inhibition. Introduction of a sulfur atom in proline and/or in the penultimate pyrrolidine rings significantly increased the inhibition, but the introduction of oxygen rather diminished the activity. A peptide linkage (acid-amide bond) between the proline and the pyrrolidine ring was also required to keep the inhibitory activity. A benzyloxycarbonyl group was most effective as an N-blocked component of the inhibitors.
Yoshimoto
T
T
School of Pharmaceutical Sciences, Nagasaki University, Japan.
Tsuru
D
D
Yamamoto
N
N
Ikezawa
R
R
Furukawa
S
S
D010450:Endopeptidases / Q000187:drug effects*; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010100:Oxygen / Q000737:chemistry; D011392:Proline / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000085822:Prolyl Oligopeptidases; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology; D012451:Safrole / Q000031:analogs & derivatives / Q000737:chemistry; D012697:Serine Endopeptidases; D015842:Serine Proteinase Inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013455:Sulfur / Q000737:chemistry
D011759:Pyrrolidines; D015842:Serine Proteinase Inhibitors; D013455:Sulfur; D011392:Proline; D010450:Endopeptidases; D012697:Serine Endopeptidases; D000085822:Prolyl Oligopeptidases; D012451:Safrole; D010100:Oxygen; C005746:sulfoxide