MEDI 470 |
| Potent and efficacious peroxisome proliferator activated receptors alpha (PPARa) activators may represent an advance in the treatment of dyslipidemia/ atherosclerosis, which are major risk factors for cardiovascular disease. Herein we wish to disclose for the first time BMS-687453, a development candidate from our PPARa program. BMS-687453 is a novel, potent PPARa selective activator. A systematic SAR study around an oxybenzylglycine skeleton 1 was explored in order to modulate PPARa and PPARg functional activity. We discovered that the regioisomeric 1,3-oxybenzylglycine compounds significantly enhanced PPARa functional activity and attenuated PPARg activity. The results of these SAR studies will be discussed in detail. BMS-687453 is a potent PPARa agonist (EC50 = 10 nM) with a high degree of selectivity vs. the PPARg receptor (EC50 = 4 µM; selectivity >400) in cell based transactivation assays. BMS-687453 has a promising pharmacokinetic profiles in preclinical animal models, with oral bioavailability of 88%, 91%, and 58% in mouse, rat, and cynomolgus monkeys, respectively. BMS-687453 also has an excellent profile in a panel of preclinical in vitro liability and toxicology assays. In pre-clinical in vivo efficacy studies, BMS-687453 robustly increased HDLc and ApoA1 levels in human ApoA1 transgenic mice and lowered VLDL and LDL cholesterol levels in dyslipidemic high fat fed hamsters. Based on its excellent potency, efficacy, pharmaceutical properties, and safety profile, BMS-687453 was advanced as a candidate for development as an agent for the treatment of dyslipidemia and atherosclerosis.
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General Oral Session
1:30 PM-4:50 PM, Thursday, August 23, 2007 BCEC -- 210A, Oral
Division of Medicinal Chemistry |
