title: Dipeptide boronic acid inhibitors of dipeptidyl peptidase IV: determinants of potency and in vivo efficacy and safety.
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.
authors.affiliation: Department of Biochemistry, Tufts University, Boston, Massachusetts 02111, USA.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Connolly
authors.forename: David G
authors.initials: DG
authors.lastname: Sanford
authors.forename: Amrita K
authors.initials: AK
authors.lastname: Chiluwal
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Healey
authors.forename: Diane E
authors.initials: DE
authors.lastname: Peters
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Dimare
authors.forename: Wengen
authors.initials: W
authors.lastname: Wu
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Liu
authors.forename: Hlaing
authors.initials: H
authors.lastname: Maw
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Zhou
authors.forename: Youhua
authors.initials: Y
authors.lastname: Li
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Jin
authors.forename: James L
authors.initials: JL
authors.lastname: Sudmeier
authors.forename: Jack H
authors.initials: JH
authors.lastname: Lai
authors.forename: William W
authors.initials: WW
authors.lastname: Bachovchin
mesh_terms: 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
chemical_list: 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