Novel inhibitors of prolyl endopeptidase: effects of stereochemistry.
Prolyl endopeptidase is a serine protease that specifically cleaves peptides on the carboxyl side of proline residues. We have show that racemic 2-(2-formyl-pyrrolidine-1-carbonyl)-2,3-dihydro-indole-1-carboxylic acid benzyl ester (IP), racemic trans-2-(2-formyl-pyrrolidine-1-carbonyl-1-cyclohexane-carboxylic acid benzyl ester (cis-CP) are slow binding inhibitors of mouse brain prolyl endopeptidase with Ki values of 0.35, 2.4, and 3 nM, respectively. In order to determine whether IP and trans/cis-CP are stereoselective in their inhibition profile, five stereoisomers were synthesized and tested for inhibition. Kinetic analysis indicates that the 2S, 2'S-isomer is necessary for inhibition by racemic IP. trans/cis-CP also requires S-stereochemistry on two of its three chiral centres; the third can be either R or S. This suggests that our novel, non-peptide inhibitors bind at the same site as peptide inhibitors which require L-configuration at the P1 and P2 binding pockets.
Kolosko
N
N
Medicinal Chemistry Department, Pfizer Central Research, Groton, CT 06340.
Bakker
A V
AV
Faraci
W S
WS
Nagel
A A
AA
D000818:Animals; D001665:Binding Sites; D007700:Kinetics; D051379:Mice; D008968:Molecular Conformation; D000085822:Prolyl Oligopeptidases; D012697:Serine Endopeptidases / Q000302:isolation & purification* / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; D000085822:Prolyl Oligopeptidases