Probing for improved selectivity with dipeptide-derived inhibitors of dipeptidyl peptidases 8 and 9: the impact of P1-variation

被引：8

作者：

Heirbaut, Leen ^{[1
]}

van Goethem, Sebastiaan ^{[1
]}

Jansen, Koen ^{[1
]}

de Winter, Hans ^{[1
]}

Lamoen, Nicole ^{[2
]}

Joossens, Jurgen ^{[1
]}

Cheng, Jonathan ^{[3
]}

Chen, Xin ^{[4
]}

Lambeir, Anne-Marie ^{[2
]}

de Meester, Ingrid ^{[2
]}

Augustyns, Koen ^{[1
]}

van der Veken, Pieter ^{[1
]}

机构：

[1] Univ Antwerp, Med Chem UAMC, Univ Pl 1, B-2610 Antwerp, Belgium

[2] Univ Antwerp, Med Biochem Lab, Univ Pl 1, B-2610 Antwerp, Belgium

[3] Fox Chase Canc Ctr, 333 Cottman Ave, Philadelphia, PA 19111 USA

[4] Natl Hlth Res Inst, 35 Keynan Rd, Zhunan 350, Miaoli County, Taiwan

来源：

MEDCHEMCOMM | 2016年 / 7卷 / 03期

关键词：

POTENT; ISOINDOLINE; LOCALIZATION;

D O I：

10.1039/c5md00454c

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Selected pyrrolidines, 2-cyanopyrrolidines and heteroaromatic isoindoline analogues were evaluated as P1-residues in dipeptide-derived inhibitors of DPP8/9. Potency testing indicates that DPP8 or DPP9 specificity cannot be obtained with the selected set of P1- and P2-fragments. Nonetheless, the nanomolar DPP8/9 potencies and remarkable selectivities with respect to DPP IV and DPPII, makes inhibitors 4c and 4h suitable "leads" for future inhibitor optimization effort.

引用

页码：433 / 438

页数：6

共 4 条

[1] Design, synthesis, and SAR of potent and selective dipeptide-derived inhibitors for dipeptidyl peptidases
Senten, K
Van der Veken, P
De Meester, I
Lambeir, AM
Scharpé, S
Haemers, A
Augustyns, K
JOURNAL OF MEDICINAL CHEMISTRY, 2003, 46 (23) : 5005 - 5014
[2] Inhibitors of dipeptidyl peptidase 8 and dipeptidyl peptidase 9.: Part 1:: Identification of dipeptide derived leads
Van der Veken, Pieter
De Meester, Ingrid
Dubois, Veronique
Soroka, Anna
Van Goethem, Sebastiaan
Maes, Marie-Berthe
Brandt, Inger
Lambeir, Anne-Marie
Chen, Xin
Haemers, Achiel
Scharpe, Simon
Augustyns, Koen
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (14) : 4154 - 4158
[3] Establishment of a dipeptidyl peptidases (DPP) 8/9 expressing cellmodel for evaluating the selectivity of DPP4 inhibitors
Huan, Yi
Jiang, Qian
Liu, Jing-long
Shen, Zhu-fang
JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS, 2015, 71 : 8 - 12
[4] Structure-Activity Relationship Studies on Isoindoline Inhibitors of Dipeptidyl Peptidases 8 and 9 (DPP8, DPP9): Is DPP8-Selectivity an Attainable Goal?
Van Goethem, Sebastiaan
Matheeussen, Veerle
Joossens, Jurgen
Lambeir, Anne-Marie
Chen, Xin
De Meester, Ingrid
Haemers, Achiel
Augustyns, Koen
Van der Veken, Pieter
JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (16) : 5737 - 5746

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