Dipeptide boronic acid inhibitors of dipeptidyl peptidase IV: determinants of potency and in vivo efficacy and safety.
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.
Connolly
Beth A
BA
Department of Biochemistry, Tufts University, Boston, Massachusetts 02111, USA.
Sanford
David G
DG
Chiluwal
Amrita K
AK
Healey
Sarah E
SE
Peters
Diane E
DE
Dimare
Matthew T
MT
Wu
Wengen
W
Liu
Yuxin
Y
Maw
Hlaing
H
Zhou
Yuhong
Y
Li
Youhua
Y
Jin
Zhiping
Z
Sudmeier
James L
JL
Lai
Jack H
JH
Bachovchin
William W
WW
D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D001897:Boronic Acids / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003001:Cloning, Molecular; D004151:Dipeptides / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D018819:Dipeptidyl Peptidase 4 / Q000097:blood / Q000302:isolation & purification; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005947:Glucose / Q000008:administration & dosage; D005951:Glucose Tolerance Test; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008968:Molecular Conformation; D019151:Peptide Library; D051381:Rats; D017207:Rats, Sprague-Dawley; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013997:Time Factors
D001786:Blood Glucose; D001897:Boronic Acids; D004151:Dipeptides; D054873:Dipeptidyl-Peptidase IV Inhibitors; D019151:Peptide Library; D015842:Serine Proteinase Inhibitors; C471241:DPP9 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D018819:Dipeptidyl Peptidase 4; D005947:Glucose