A 24-WEEK, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER STUDY OF THE SAFETY AND EFFICACY OF PPM-204 IN SUBJECTS WITH TYPE 2 DIABETES - ND

Start Date26 Apr 2007

Sponsor / Collaborator-

NCT00425919 / TerminatedPhase 2

A 24-Week, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study Of The Safety And Efficacy Of PPM-204 In Subjects With Type 2 Diabetes

The purpose of this study is to learn whether PPM-204 has an effect on lowering blood glucose (blood sugar) levels and is safe in treating people with type 2 diabetes.

Start Date01 Jan 2007

Sponsor / Collaborator

Wyeth AB

100 Clinical Results associated with Indeglitazar

100 Translational Medicine associated with Indeglitazar

100 Patents (Medical) associated with Indeglitazar

Literatures (Medical) associated with Indeglitazar

01 Dec 2023·Bioorganic & Medicinal Chemistry

Design, synthesis, and biological evaluation of deuterated indolepropionic acid derivatives as novel long-acting pan PPARα/γ/δ agonists

Article

Author: Sun, Lidan ; Wang, Bin ; Wang, Guangji ; Yang, Zhongcheng ; Li, Zheng ; Chen, Ya ; Cai, Zongyu ; Chen, Lianru ; Wang, Xuekun

Metabolic syndrome is a complex disease with diverse symptoms, but current pharmacological interventions have limited efficacy. Indeglitazar, a pan-agonist targeting the three-peroxisome proliferator activated receptors (PPAR), exhibits significant therapeutic effects on both diabetic and fatty liver animal models. However, its short half-life limits the in vivo efficacy, which might be attributed to the β-oxidation of indolepropionic acid at Indeglitazar. To overcome this metabolic instability, two deuterium atoms were introduced to the α-position of indolepropionic acid to block the β-oxidation. In this study, several deuterated derivatives were found to sustain PPARs activity and extend the half-life of liver microsomes. In oral glucose tolerance tests, I-1 exhibited the strongest glucose-lowering effect on ob/ob mice in this series. In db/db mice, I-1 reduced lipid levels, liver steatosis and promoted UCP1 expression in white adipose tissue. Mechanistic studies further revealed that I-1 exerts stronger effects than Indeglitazar on the regulation of genes related to lipid metabolism, mitochondrial function, and oxidative stress. Furthermore, I-1 significantly reduced liver steatosis, hepatocellular ballooning, inflammation, and fibrosis in NASH model induced by HFD + CCl₄, and even exerted better therapeutic effect than that of Indeglitazar. With the above attractive efficacy, deuterated derivative I-1 is considered as a promising treatment for metabolic syndrome.

06 Jan 2009·Proceedings of the National Academy of SciencesQ1 · CROSS-FIELD

Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent

Q1 · CROSS-FIELD

Article

Author: West, Brian L. ; Zhang, Chao ; Womack, Patrick ; Signaevsky, Maxime ; Perreault, Mylene ; Tobin, James F. ; Mehra, Upasana ; England, Bruce P. ; Shi, Shenghua ; Wang, Weiru ; Powell, Benjamin ; Nolop, Keith ; Habets, Gaston ; Arnold, James ; Kral, John ; Nguyen, Hoa ; Vlasuk, George P. ; Zhang, Kam Y. J. ; Lin, Jack J. ; Plotnikov, Alexander N. ; Ibrahim, Prabha N. ; Krupka, Heike I. ; Will, Sarah ; Settachatgull, Calvin ; Erbe, David ; Bollag, Gideon ; Milburn, Michael V. ; Fong, Daniel ; Yan, Douglas S. ; Oh, Angela ; Marimuthu, Adhirai ; Cantwell, John ; Hirth, K. Peter ; Artis, Dean R.

In a search for more effective anti-diabetic treatment, we used a process coupling low-affinity biochemical screening with high-throughput co-crystallography in the design of a series of compounds that selectively modulate the activities of all three peroxisome proliferator-activated receptors (PPARs), PPARα, PPARγ, and PPARδ. Transcriptional transactivation assays were used to select compounds from this chemical series with a bias toward partial agonism toward PPARγ, to circumvent the clinically observed side effects of full PPARγ agonists. Co-crystallographic characterization of the lead molecule, indeglitazar, in complex with each of the 3 PPARs revealed the structural basis for its PPAR pan-activity and its partial agonistic response toward PPARγ. Compared with full PPARγ-agonists, indeglitazar is less potent in promoting adipocyte differentiation and only partially effective in stimulating adiponectin gene expression. Evaluation of the compound in vivo confirmed the reduced adiponectin response in animal models of obesity and diabetes while revealing strong beneficial effects on glucose, triglycerides, cholesterol, body weight, and other metabolic parameters. Indeglitazar has now progressed to Phase II clinical evaluations for Type 2 diabetes mellitus (T2DM).

100 Deals associated with Indeglitazar

External Link

KEGG	Wiki	ATC	Drug Bank
D09350	-	-	DB07724

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Mellitus	Phase 2	JP	Wyeth AB	01 Nov 2006
Diabetes Mellitus, Type 2	Phase 2	US	Plexxikon, Inc.	-

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