Author: Muckelbauer, Jodi ; Li, Jun ; Locke, Kenneth T. ; Meyers, Daniel S. ; 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 ; Mukherjee, Ranjan ; Zhang, Litao ; Kennedy, Lawrence J. ; Li, Yi-Xin ; 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.

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

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