Structure-activity relationships of boronic acid inhibitors of dipeptidyl peptidase IV. 1. Variation of the P2 position of Xaa-boroPro dipeptides.
A series of prolineboronic acid (boroPro) containing dipeptides were synthesized and assayed for their ability to inhibit the serine protease dipeptidyl peptidase IV (DPPIV). Inhibitory activity, which requires the (R)-stereoisomer of boroPro in the P1 position, appears to tolerate a variety of L-amino acids in the P2 position. Substitution at the P2 position which is not tolerated include the D-amino acids, alpha,alpha-disubstituted amino acids, and glycine. Specificity against DPPII and proline specific endopeptidase is reported. A correlation between the ability to inhibit DPPIV in cell culture and in the human mixed lymphocyte reaction is demonstrated. A synthesis of prolineboronic acid is reported as well as conditions for generating the fully unprotected boronic acid dipeptides in either their cyclic or acyclic forms.
Coutts
S J
SJ
Research and Development Center, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut 06877, USA.
Kelly
T A
TA
Snow
R J
RJ
Kennedy
C A
CA
Barton
R W
RW
Adams
J
J
Krolikowski
D A
DA
Freeman
D M
DM
Campbell
S J
SJ
Ksiazek
J F
JF
Bachovchin
W W
WW
D001897:Boronic Acids / Q000737:chemistry* / Q000494:pharmacology*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007959:Lymphocyte Culture Test, Mixed; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001897:Boronic Acids; D004791:Enzyme Inhibitors; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases