Dipeptide Boronic Acid Inhibitors of Dipeptidyl Peptidase IV: Determinants of Potency and in Vivo Efficacy and Safety

• Published in: Journal of medicinal chemistry Vol. 51; no. 19; pp. 6005 - 6013
• Main Authors: Connolly, Beth A, Sanford, David G, Chiluwal, Amrita K, Healey, Sarah E, Peters, Diane E, Dimare, Matthew T, Wu, Wengen, Liu, Yuxin, Maw, Hlaing, Zhou, Yuhong, Li, Youhua, Jin, Zhiping, Sudmeier, James L, Lai, Jack H, Bachovchin, William W
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.10.2008; Amer Chemical Soc
• Subjects: Administration, Oral; Animals; Biological and medical sciences; Blood Glucose - analysis; Blood Glucose - metabolism; Boronic Acids - administration & dosage; Boronic Acids - chemistry; Boronic Acids - pharmacology; Cell Line; Chemistry, Medicinal; 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; General and cellular metabolism. Vitamins; Glucose - administration & dosage; Glucose Tolerance Test; Humans; Life Sciences & Biomedicine; Male; Medical sciences; Mice; Mice, Inbred C57BL; Molecular Conformation; Peptide Library; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Science & Technology; Serine Proteinase Inhibitors - administration & dosage; Serine Proteinase Inhibitors - chemistry; Serine Proteinase Inhibitors - pharmacology; Structure-Activity Relationship; Substrate Specificity; Time Factors; BOROPRO; LOCALIZATION; SUBSTRATE-SPECIFICITY; GLUCAGON-LIKE PEPTIDE-1; ACTIVE-SITE; ENDOPEPTIDASE; DEGRADATION; AMINOPEPTIDASE; MECHANISMS; FIBROBLAST ACTIVATION PROTEIN; Type 2 diabetes; Dipeptidyl-peptidase IV; Peptides; Enzyme; Toxicity; Rodentia; Metabolic diseases; Glucose tolerance test; Biological activity; Peptidases; In vivo; Vertebrata; Mammalia; Mouse; Animal; Substrate specificity; Dipeptides; Hydrolases; Boron Organic compounds; Inhibitor; Boronic acids
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm800390n

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.