Dipeptide boronic acid inhibitors of dipeptidyl peptidase IV: determinants of potency and in vivo efficacy and safety

Beth A Connolly; David G Sanford; Amrita K Chiluwal; Sarah E Healey; Diane E Peters; Matthew T Dimare; Wengen Wu; Yuxin Liu; Hlaing Maw; Yuhong Zhou; Youhua Li; Zhiping Jin; James L Sudmeier; Jack H Lai; William W Bachovchin

doi:10.1021/jm800390n

Dipeptide boronic acid inhibitors of dipeptidyl peptidase IV: determinants of potency and in vivo efficacy and safety

J Med Chem. 2008 Oct 9;51(19):6005-13. doi: 10.1021/jm800390n. Epub 2008 Sep 11.

Authors

Beth A Connolly¹, David G Sanford, Amrita K Chiluwal, Sarah E Healey, Diane E Peters, Matthew T Dimare, Wengen Wu, Yuxin Liu, Hlaing Maw, Yuhong Zhou, Youhua Li, Zhiping Jin, James L Sudmeier, Jack H Lai, William W Bachovchin

Affiliation

¹ Department of Biochemistry, Tufts University, Boston, Massachusetts 02111, USA.

PMID: 18783201
DOI: 10.1021/jm800390n

Abstract

Dipeptidyl peptidase IV (DPP-IV; E.C. 3.4.14.5), a serine protease that degrades the incretin hormones GLP-1 and GIP, is now a validated target for the treatment of type 2 diabetes. Dipeptide boronic acids, among the first, and still among the most potent DPP-IV inhibitors known, suffer from a concern over their safety. Here we evaluate the potency, in vivo efficacy, and safety of a selected set of these inhibitors. The adverse effects induced by boronic acid-based DPP-IV inhibitors are essentially limited to what has been observed previously for non-boronic acid inhibitors and attributed to cross-reactivity with DPP8/9. While consistent with the DPP8/9 hypothesis, they are also consistent with cross-reactivity with some other intracellular target. The results further show that the potency of simple dipeptide boronic acid-based inhibitors can be combined with selectivity against DPP8/9 in vivo to produce agents with a relatively wide therapeutic index (>500) in rodents.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Animals
Blood Glucose / analysis
Blood Glucose / metabolism
Boronic Acids / administration & dosage*
Boronic Acids / chemistry
Boronic Acids / pharmacology
Cell Line
Cloning, Molecular
Dipeptides / administration & dosage*
Dipeptides / chemistry
Dipeptides / pharmacology
Dipeptidyl Peptidase 4 / blood
Dipeptidyl Peptidase 4 / isolation & purification
Dipeptidyl-Peptidase IV Inhibitors
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / antagonists & inhibitors
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / biosynthesis
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Drug-Related Side Effects and Adverse Reactions
Female
Glucose / administration & dosage
Glucose Tolerance Test
Humans
Male
Mice
Mice, Inbred C57BL
Molecular Conformation
Peptide Library
Rats
Rats, Sprague-Dawley
Serine Proteinase Inhibitors / administration & dosage*
Serine Proteinase Inhibitors / chemistry
Serine Proteinase Inhibitors / pharmacology
Structure-Activity Relationship
Substrate Specificity
Time Factors

Substances

Blood Glucose
Boronic Acids
Dipeptides
Dipeptidyl-Peptidase IV Inhibitors
Peptide Library
Serine Proteinase Inhibitors
DPP9 protein, human
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
Dipeptidyl Peptidase 4
Glucose