Author: Muckelbauer, Jodi ; Li, Jun ; Meyers, Daniel S. ; Locke, Kenneth T. ; Lim, Ngiap-Kie ; Krystek, Stanley R. ; Chang, Chiehying ; O’Malley, Kevin M. ; Shi, Yan ; Hernández, Andrés S. ; Kadiyala, Pathanjali ; Grimm, Denise ; Blanar, Michael A. ; Zhang, Rongan ; Zhang, Litao ; Mukherjee, Ranjan ; Li, Yi-Xin ; Kennedy, Lawrence J. ; Monshizadegan, Hossain ; Zahler, Robert ; Tao, Shiwei ; Xu, Carrie ; Wong, Henry ; Harrity, Thomas ; Chen, Bang-Chi ; Hosagrahara, Vinayak ; Miao, Bowman ; Cheng, Peter T. W. ; Zhang, Huiping ; Zhu, Juliang ; Tino, Joseph A. ; Trehan, Ashok ; Srivastava, Rai Ajit ; Lai, Zhi ; Chen, Sean ; Zhang, Lisa ; Kunselman, Lori K. ; Cap, Michael ; Search, Debra

BMS-711939 (3) is a potent and selective peroxisome proliferator-activated receptor (PPAR) α agonist, with an EC50 of 4 nM for human PPARα and >1000-fold selectivity vs human PPARγ (EC50 = 4.5 μM) and PPARδ (EC50 > 100 μM) in PPAR-GAL4 transactivation assays. Compound 3 also demonstrated excellent in vivo efficacy and safety profiles in preclinical studies and thus was chosen for further preclinical evaluation. The synthesis, structure-activity relationship (SAR) studies, and in vivo pharmacology of 3 in preclinical animal models as well as its ADME profile are described.

01 Dec 2008·Journal of Pharmacology and Experimental TherapeuticsQ3 · MEDICINE

Novel Peroxisome Proliferator-Activated Receptor α Agonists Lower Low-Density Lipoprotein and Triglycerides, Raise High-Density Lipoprotein, and Synergistically Increase Cholesterol Excretion with a Liver X Receptor Agonist

Q3 · MEDICINE

Article

Author: Miao, Bowman ; Tino, Joseph ; Li, Jun ; Mukherjee, Ranjan ; Shi, Yan ; Search, Debra ; Kennedy, Lawrence J. ; Flynn, Michael ; Zhang, Litao ; Blanar, Michael ; Grimm, Denise ; Cheng, Peter T. ; Srivastava, Rai Ajit ; O'Malley, Kevin M. ; Zhang, Rongan ; Locke, Kenneth T. ; Meyers, Daniel ; Monshizadegan, Hossain

The first generation peroxisome proliferator-activated receptor (PPAR) alpha agonist gemfibrozil reduces the risk of major cardiovascular events; therefore, more potent PPARalpha agonists for the treatment of cardiovascular diseases have been actively sought. We describe two novel, potent oxybenzylglycine PPARalpha-selective agonists, BMS-687453 [N-[[3-[[2-(4-chlorophenyl)-5-methyl-4-oxazolyl]methoxy]phenyl]methyl]-N-(methoxycarbonyl)-glycine] and BMS-711939 N-[[5-[[2-(4-chlorophenyl)-5-methyl-4-oxazolyl]methoxy]-2-fluorophenyl]methyl]-N-(methoxycarbonyl)-glycine], that robustly increase apolipoprotein (Apo) A1 and high-density lipoprotein cholesterol in human ApoA1 transgenic mice and lower low-density lipoprotein-cholesterol and triglycerides in fat-fed hamsters. These compounds have much lower potency against mouse PPARalpha than human PPARalpha; therefore, they were tested in PPARalpha-humanized mice that do not express murine PPARalpha but express human PPARalpha selectively in the liver. We developed hepatic gene induction as a novel biomarker for efficacy and demonstrate hepatic gene induction at very low doses of these compounds. BMS-711939 induces fecal cholesterol excretion, which is further increased upon cotreatment with a liver X receptor (LXR) agonist. It is surprising that this synergistic increase upon coadministration is also observed in mice that express PPARalpha in the liver only. BMS-711939 also prevented the LXR agonist-induced elevation of serum triglycerides. Such PPARalpha agonists could be attractive candidates to explore for the treatment of cardiovascular diseases, especially in combination with a suitable LXR agonist.

100 Deals associated with BMS-711939

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Dyslipidemias	Preclinical	GB	Bristol-Myers Squibb Pharmaceuticals Ltd.	09 Jun 2016

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

BMS-711939

Overview

Basic Info

Structure

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation