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2-(4-carbonylphenyl)benzoxazole inhibitors of CETP: scaffold design and advancement in HDLc-raising efficacy |
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| Authors: | Sweis Ramzi F Hunt Julianne A Kallashi Florida Hammond Milton L Chen Ying Eveland Suzanne S Guo Qiu Hyland Sheryl A Milot Denise P Cumiskey Anne-Marie Latham Melanie Rosa Raymond Peterson Larry Sparrow Carl P Wright Samuel D Anderson Matt S Sinclair Peter J |
| Institution: | a Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA b Department of Cardiovascular Diseases, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA c Department of Pharmacology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA (ES) |
| Abstract: | The development of 2-phenylbenzoxazoles as inhibitors of cholesteryl ester transfer protein (CETP) is described. Initial efforts aimed at engineering replacements for the aniline substructures in the benchmark molecule. Reversing the connectivity of the central aniline lead to a new class of 2-(4-carbonylphenyl)benzoxazoles. Structure-activity studies at the C-7 and terminal pyridine ring allowed for the optimization of potency and HDLc-raising efficacy in this new class of inhibitors. These efforts lead to the discovery of benzoxazole 11v, which raised HDLc by 24 mg/dl in our transgenic mouse PD model. |
| Keywords: | Cholesteryl ester transfer protein Cholesterol HDLc LDLc Atherosclerosis Lipid |
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