title: Phenoxyphenyl sulfone N-formylhydroxylamines (retrohydroxamates) as potent, selective, orally bioavailable matrix metalloproteinase inhibitors.
abstract: A novel series of sulfone N-formylhydroxylamines (retrohydroxamates) have been investigated as matrix metalloproteinases (MMP) inhibitors. The substitution of the ether linkage of ABT-770 (5) with a sulfone group 13a led to a substantial increase in activity against MMP-9 but was accompanied by a loss of selectivity for inhibition of MMP-2 and -9 over MMP-1 and diminished oral exposure. Replacement of the biphenyl P1' substituent with a phenoxyphenyl group provided compounds that are highly selective for inhibition of MMP-2 and -9 over MMP-1. Optimization of the substituent adjacent to the retrohydroxamate center in this series led to the clinical candidate ABT-518 (6), a highly potent, selective, orally bioavailable MMP inhibitor that has been shown to significantly inhibit tumor growth in animal cancer models.
authors.affiliation: Cancer Research Area, Abbott Laboratories, Department 47J, Building AP10, 100 Abbott Park Road, Abbott Park, Illinois 60064-6100, USA. carol.wada@abbott.com
authors.forename: Carol K
authors.initials: CK
authors.lastname: Wada
authors.forename: James H
authors.initials: JH
authors.lastname: Holms
authors.forename: Michael L
authors.initials: ML
authors.lastname: Curtin
authors.forename: Yujia
authors.initials: Y
authors.lastname: Dai
authors.forename: Alan S
authors.initials: AS
authors.lastname: Florjancic
authors.forename: Robert B
authors.initials: RB
authors.lastname: Garland
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.forename: H Robin
authors.initials: HR
authors.lastname: Heyman
authors.forename: Jamie R
authors.initials: JR
authors.lastname: Stacey
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Steinman
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Albert
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Bouska
authors.forename: Ildiko N
authors.initials: IN
authors.lastname: Elmore
authors.forename: Carole L
authors.initials: CL
authors.lastname: Goodfellow
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Marcotte
authors.forename: Paul
authors.initials: P
authors.lastname: Tapang
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Morgan
authors.forename: Michael R
authors.initials: MR
authors.lastname: Michaelides
authors.forename: Steven K
authors.initials: SK
authors.lastname: Davidsen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D002460:Cell Line; D005559:Formamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006898:Hydroxylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008252:Macaca fascicularis; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D005559:Formamides; D006898:Hydroxylamines; D061965:Matrix Metalloproteinase Inhibitors; C443806:N-(1-(2,2-dimethyl-1,3-dioxol-4-yl)-2-((4,4-(trifluoromethoxyphenoxy)phenyl)sulfonyl)ethyl)-N-hydroxyformamide; D011480:Protease Inhibitors; D014409:Tumor Necrosis Factor-alpha; D008666:Metalloendopeptidases