Boro-norleucine as a P1 residue for the design of selective and potent DPP7 inhibitors

Kevin R Shreder; Melissa S Wong; Sergio Corral; Zhizhou Yu; David T Winn; Min Wu; Yi Hu; Tyzoon Nomanbhoy; Senaiet Alemayehu; Stacy R Fuller; Jonathan S Rosenblum; John W Kozarich

doi:10.1016/j.bmcl.2005.06.076

Boro-norleucine as a P1 residue for the design of selective and potent DPP7 inhibitors

Bioorg Med Chem Lett. 2005 Oct 1;15(19):4256-60. doi: 10.1016/j.bmcl.2005.06.076.

Authors

Kevin R Shreder¹, Melissa S Wong, Sergio Corral, Zhizhou Yu, David T Winn, Min Wu, Yi Hu, Tyzoon Nomanbhoy, Senaiet Alemayehu, Stacy R Fuller, Jonathan S Rosenblum, John W Kozarich

Affiliation

¹ ActivX Biosciences, 11025 N. Torrey Pines Road, La Jolla, CA 92037, USA. kevins@activx.com

PMID: 16084722
DOI: 10.1016/j.bmcl.2005.06.076

Abstract

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.

MeSH terms

Boronic Acids*
Dipeptides / chemical synthesis
Dipeptides / pharmacology
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / antagonists & inhibitors*
Drug Design
Humans
Inhibitory Concentration 50
Norleucine / analogs & derivatives*
Norleucine / pharmacology
Structure-Activity Relationship
Substrate Specificity

Substances

Boronic Acids
Dipeptides
Norleucine
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
dipeptidyl peptidase II