D-420720, a novel orally active sulfonamide compound dipeptidyl peptidase IV inhibitor

Structure and activity relationship of arylsulfonamide to dipeptidyl peptidase IV inhibition

Henry J. Tsai, Shan Yen Chou, Shih Hsien Chuang, Chien Cheng Chen, Feng Lin Hsu

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Diabetes mellitus is a chronic disease characteristic of poor glucose homeostasis that requires constant monitoring and adjustment of blood glucose levels by exogenous intervention. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are two incretin peptide hormones secreted from the intestine to synergize insulin's function at lowering blood glucose. The effects of GLP-1 or GIP administration are short-lived because they are rapidly inactivated by circulating dipeptidyl peptidase IV (DPP-IV). Therefore, DPP-IV inhibitors have been suggested to be a new class of molecule for treating hyperglycemic conditions in diabetic patients. The recent approval of Merck's Sitagliptin (a DPP-IV-specific inhibitor) indicates that DPP-IV inhibition is a good target for new therapeutic agent development. The present study was conducted to evaluate the efficacies of a series of dipeptidyl derivatives with a sulfonamide moiety as DPP-IV inhibitors. Among these compounds, D-420720 was a potent inhibitor (Ki = 39 nM), with a selectivity of 9160-fold over the DPP-II isozyme and elicits a hypoglycemic effect on oral glucose tolerance test with normal male ICR mice.

Original languageEnglish
Pages (from-to)514-519
Number of pages6
JournalDrug Development Research
Volume69
Issue number8
DOIs
Publication statusPublished - Dec 2008

Fingerprint

Dipeptidyl-Peptidase IV Inhibitors
Dipeptidyl Peptidase 4
Sulfonamides
Structure-Activity Relationship
Gastric Inhibitory Polypeptide
Glucagon-Like Peptide 1
Blood Glucose
Incretins
Inbred ICR Mouse
Peptide Hormones
Glucose Tolerance Test
Hypoglycemic Agents
Isoenzymes
Intestines
Diabetes Mellitus
Homeostasis
Chronic Disease
Glucose
Therapeutics

Keywords

  • Diabetes
  • Dipeptidyl peptidase IV
  • Inhibitor
  • Sulfonamide

ASJC Scopus subject areas

  • Drug Discovery

Cite this

D-420720, a novel orally active sulfonamide compound dipeptidyl peptidase IV inhibitor : Structure and activity relationship of arylsulfonamide to dipeptidyl peptidase IV inhibition. / Tsai, Henry J.; Chou, Shan Yen; Chuang, Shih Hsien; Chen, Chien Cheng; Hsu, Feng Lin.

In: Drug Development Research, Vol. 69, No. 8, 12.2008, p. 514-519.

Research output: Contribution to journalArticle

@article{d19450fa62c34f18ac390a966977cbce,
title = "D-420720, a novel orally active sulfonamide compound dipeptidyl peptidase IV inhibitor: Structure and activity relationship of arylsulfonamide to dipeptidyl peptidase IV inhibition",
abstract = "Diabetes mellitus is a chronic disease characteristic of poor glucose homeostasis that requires constant monitoring and adjustment of blood glucose levels by exogenous intervention. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are two incretin peptide hormones secreted from the intestine to synergize insulin's function at lowering blood glucose. The effects of GLP-1 or GIP administration are short-lived because they are rapidly inactivated by circulating dipeptidyl peptidase IV (DPP-IV). Therefore, DPP-IV inhibitors have been suggested to be a new class of molecule for treating hyperglycemic conditions in diabetic patients. The recent approval of Merck's Sitagliptin (a DPP-IV-specific inhibitor) indicates that DPP-IV inhibition is a good target for new therapeutic agent development. The present study was conducted to evaluate the efficacies of a series of dipeptidyl derivatives with a sulfonamide moiety as DPP-IV inhibitors. Among these compounds, D-420720 was a potent inhibitor (Ki = 39 nM), with a selectivity of 9160-fold over the DPP-II isozyme and elicits a hypoglycemic effect on oral glucose tolerance test with normal male ICR mice.",
keywords = "Diabetes, Dipeptidyl peptidase IV, Inhibitor, Sulfonamide",
author = "Tsai, {Henry J.} and Chou, {Shan Yen} and Chuang, {Shih Hsien} and Chen, {Chien Cheng} and Hsu, {Feng Lin}",
year = "2008",
month = "12",
doi = "10.1002/ddr.20278",
language = "English",
volume = "69",
pages = "514--519",
journal = "Drug Development Research",
issn = "0272-4391",
publisher = "John Wiley and Sons Inc.",
number = "8",

}

TY - JOUR

T1 - D-420720, a novel orally active sulfonamide compound dipeptidyl peptidase IV inhibitor

T2 - Structure and activity relationship of arylsulfonamide to dipeptidyl peptidase IV inhibition

AU - Tsai, Henry J.

AU - Chou, Shan Yen

AU - Chuang, Shih Hsien

AU - Chen, Chien Cheng

AU - Hsu, Feng Lin

PY - 2008/12

Y1 - 2008/12

N2 - Diabetes mellitus is a chronic disease characteristic of poor glucose homeostasis that requires constant monitoring and adjustment of blood glucose levels by exogenous intervention. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are two incretin peptide hormones secreted from the intestine to synergize insulin's function at lowering blood glucose. The effects of GLP-1 or GIP administration are short-lived because they are rapidly inactivated by circulating dipeptidyl peptidase IV (DPP-IV). Therefore, DPP-IV inhibitors have been suggested to be a new class of molecule for treating hyperglycemic conditions in diabetic patients. The recent approval of Merck's Sitagliptin (a DPP-IV-specific inhibitor) indicates that DPP-IV inhibition is a good target for new therapeutic agent development. The present study was conducted to evaluate the efficacies of a series of dipeptidyl derivatives with a sulfonamide moiety as DPP-IV inhibitors. Among these compounds, D-420720 was a potent inhibitor (Ki = 39 nM), with a selectivity of 9160-fold over the DPP-II isozyme and elicits a hypoglycemic effect on oral glucose tolerance test with normal male ICR mice.

AB - Diabetes mellitus is a chronic disease characteristic of poor glucose homeostasis that requires constant monitoring and adjustment of blood glucose levels by exogenous intervention. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are two incretin peptide hormones secreted from the intestine to synergize insulin's function at lowering blood glucose. The effects of GLP-1 or GIP administration are short-lived because they are rapidly inactivated by circulating dipeptidyl peptidase IV (DPP-IV). Therefore, DPP-IV inhibitors have been suggested to be a new class of molecule for treating hyperglycemic conditions in diabetic patients. The recent approval of Merck's Sitagliptin (a DPP-IV-specific inhibitor) indicates that DPP-IV inhibition is a good target for new therapeutic agent development. The present study was conducted to evaluate the efficacies of a series of dipeptidyl derivatives with a sulfonamide moiety as DPP-IV inhibitors. Among these compounds, D-420720 was a potent inhibitor (Ki = 39 nM), with a selectivity of 9160-fold over the DPP-II isozyme and elicits a hypoglycemic effect on oral glucose tolerance test with normal male ICR mice.

KW - Diabetes

KW - Dipeptidyl peptidase IV

KW - Inhibitor

KW - Sulfonamide

UR - http://www.scopus.com/inward/record.url?scp=58449107784&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=58449107784&partnerID=8YFLogxK

U2 - 10.1002/ddr.20278

DO - 10.1002/ddr.20278

M3 - Article

VL - 69

SP - 514

EP - 519

JO - Drug Development Research

JF - Drug Development Research

SN - 0272-4391

IS - 8

ER -