Boro-norleucine as a P1 residue for the design of selective and potent DPP7 inhibitors.
Dipeptide-based inhibitors with C-substituted (alkyl or aminoalkyl) alpha-amino acids in the P2 position and boro-norleucine (boro-Nle) in the P1 position were synthesized. Relative to boro-proline, boro-Nle as a P1 residue was shown able to significantly dial out DPP4, FAP, DPP8, and DPP9 activity. Dab-boro-Nle (4g) proved to be the most selective and potent DPP7 inhibitor with a DPP7 IC50 value of 480 pM.
Shreder
Kevin R
KR
ActivX Biosciences, 11025 N. Torrey Pines Road, La Jolla, CA 92037, USA. kevins@activx.com
Wong
Melissa S
MS
Corral
Sergio
S
Yu
Zhizhou
Z
Winn
David T
DT
Wu
Min
M
Hu
Yi
Y
Nomanbhoy
Tyzoon
T
Alemayehu
Senaiet
S
Fuller
Stacy R
SR
Rosenblum
Jonathan S
JS
Kozarich
John W
JW
D001897:Boronic Acids; D004151:Dipeptides / Q000138:chemical synthesis / Q000494:pharmacology; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors*; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D009646:Norleucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D001897:Boronic Acids; D004151:Dipeptides; D009646:Norleucine; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C100151:dipeptidyl peptidase II