title: Picornavirus inhibitors: trifluoromethyl substitution provides a global protective effect against hepatic metabolism.
abstract: Several modifications of the oxazoline ring of WIN 54954, a broad spectrum antipicornavirus compound, have been prepared in order to address the acid lability and metabolic instability of this compound. We have previously shown that the oxadiazole analogue 3 displayed comparable activity against a variety of rhinoviruses and appeared to be stable to acid. A monkey liver microsomal assay was developed to examine the metabolic stability in vitro of both compounds, and it was determined that WIN 54954 displayed 18 metabolic products while 3 was converted to 8 products. Two major products of 3 were determined by LC-MS/MS to be monohydroxylated at each of the terminal methyl groups. Replacement of the methyl on the isoxazole ring with a trifluoromethyl group, while preventing hydroxylation at this position, did not reduce the sensitivity of the molecule to microsomal metabolism at other sites. However, the (trifluoromethyl)oxadiazole 9 not only prevented hydroxylation at this position but also provided protection at the isoxazole end of the molecule, resulting in only two minor products to the extent of 4%. The major product was identified as the monohydroxylated compound 23. The global metabolic protective effect of trifluoromethyl group on the oxadiazole ring was further demonstrated by examining a variety of analogues including heterocyclic replacements of the isoxazole ring. In each case, the trifluoromethyl analogue displayed a protective effect when compared to the corresponding methyl analogue.
authors.affiliation: Research Division Sanofi Winthrop, Inc., Collegeville, Pennsylvania 19426, USA.
authors.forename: G D
authors.initials: GD
authors.lastname: Diana
authors.forename: P
authors.initials: P
authors.lastname: Rudewicz
authors.forename: D C
authors.initials: DC
authors.lastname: Pevear
authors.forename: T J
authors.initials: TJ
authors.lastname: Nitz
authors.forename: S C
authors.initials: SC
authors.lastname: Aldous
authors.forename: D J
authors.initials: DJ
authors.lastname: Aldous
authors.forename: D T
authors.initials: DT
authors.lastname: Robinson
authors.forename: T
authors.initials: T
authors.lastname: Draper
authors.forename: F J
authors.initials: FJ
authors.lastname: Dutko
authors.forename: C
authors.initials: C
authors.lastname: Aldi
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D005617:Chlorofluorocarbons, Methane / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003196:Computer Graphics; D000882:Haplorhini; D007555:Isoxazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry / Q000379:methods; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D010849:Picornaviridae / Q000187:drug effects*; D013055:Spectrophotometry, Infrared
chemical_list: D000998:Antiviral Agents; D005617:Chlorofluorocarbons, Methane; D007555:Isoxazoles; C062554:Win 54954; C009554:fluoroform