title: 2-(4-Carbonylphenyl)benzoxazole inhibitors of CETP: attenuation of hERG binding and improved HDLc-raising efficacy.
abstract: The development of 2-phenylbenzoxazoles as inhibitors of cholesteryl ester transfer protein (CETP) is described. Efforts focused on finding suitable replacements for the central piperidine with the aim of reducing hERG binding: a main liability of our benchmark benzoxazole (1a). Replacement of the piperidine with a cyclohexyl group successfully attenuated hERG binding, but was accompanied by reduced in vivo efficacy. The approach of substituting a piperidine moiety with an oxazolidinone also attenuated hERG binding. Further refinement of this latter scaffold via SAR at the pyridine terminus and methyl branching on the oxazolidinone led to compounds 7e and 7f, which raised HDLc by 33 and 27mg/dl, respectively, in our transgenic mouse PD model and without the hERG liability of previous series.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. rfsweis@gmail.com
authors.forename: Ramzi F
authors.initials: RF
authors.lastname: Sweis
authors.forename: Julianne A
authors.initials: JA
authors.lastname: Hunt
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sinclair
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Suzanne S
authors.initials: SS
authors.lastname: Eveland
authors.forename: Qiu
authors.initials: Q
authors.lastname: Guo
authors.forename: Sheryl A
authors.initials: SA
authors.lastname: Hyland
authors.forename: Denise P
authors.initials: DP
authors.lastname: Milot
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Cumiskey
authors.forename: Melanie
authors.initials: M
authors.lastname: Latham
authors.forename: Raymond
authors.initials: R
authors.lastname: Rosa
authors.forename: Larry
authors.initials: L
authors.lastname: Peterson
authors.forename: Carl P
authors.initials: CP
authors.lastname: Sparrow
authors.forename: Matt S
authors.initials: MS
authors.lastname: Anderson
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D008076:Cholesterol, HDL / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D051379:Mice; D008822:Mice, Transgenic; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000378:metabolism*; D000071230:Transcriptional Regulator ERG
chemical_list: D001583:Benzoxazoles; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; C072312:ERG protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG