title: The synthesis of novel matrix metalloproteinase inhibitors employing the Ireland-Claisen rearrangement.
abstract: Matrix metalloproteinase inhibitors of general formula (1) were synthesised by a route involving an Ireland-Claisen rearrangement which enables systematic modification of the substituent alpha to the hydroxamic acid. An analogue (12c) possessing an alpha-cyclopentyl group is a potent broad spectrum inhibitor that displays high and sustained blood levels following oral dosing in both the rat and marmoset ex-vivo bioassays. This compound and analogues are also potent inhibitors of TNF alpha release.
authors.affiliation: British Biotech Pharmaceuticals Limited, Cowley, Oxford.
authors.forename: L M
authors.initials: LM
authors.lastname: Pratt
authors.forename: R P
authors.initials: RP
authors.lastname: Beckett
authors.forename: C L
authors.initials: CL
authors.lastname: Bellamy
authors.forename: D J
authors.initials: DJ
authors.lastname: Corkill
authors.forename: J
authors.initials: J
authors.lastname: Cossins
authors.forename: P F
authors.initials: PF
authors.lastname: Courtney
authors.forename: S J
authors.initials: SJ
authors.lastname: Davies
authors.forename: A H
authors.initials: AH
authors.lastname: Davidson
authors.forename: A H
authors.initials: AH
authors.lastname: Drummond
authors.forename: K
authors.initials: K
authors.lastname: Helfrich
authors.forename: C N
authors.initials: CN
authors.lastname: Lewis
authors.forename: M
authors.initials: M
authors.lastname: Mangan
authors.forename: F M
authors.initials: FM
authors.lastname: Martin
authors.forename: K
authors.initials: K
authors.lastname: Miller
authors.forename: P
authors.initials: P
authors.lastname: Nayee
authors.forename: M L
authors.initials: ML
authors.lastname: Ricketts
authors.forename: W
authors.initials: W
authors.lastname: Thomas
authors.forename: R S
authors.initials: RS
authors.lastname: Todd
authors.forename: M
authors.initials: M
authors.lastname: Whittaker
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002144:Callithrix; D003864:Depression, Chemical; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D006877:Hydroxamic Acids; D008070:Lipopolysaccharides; D011480:Protease Inhibitors; D014409:Tumor Necrosis Factor-alpha; D008666:Metalloendopeptidases