title: NMR-based modification of matrix metalloproteinase inhibitors with improved bioavailability.
abstract: The NMR-based discovery of biaryl hydroxamate inhibitors of the matrix metalloproteinase stromelysin (MMP-3) has been previously described (Hajduk et al. J. Am. Chem. Soc. 1997, 119, 5818-5827). While potent in vitro, these inhibitors exhibited no in vivo activity due, at least in part, to the poor pharmacokinetic properties of the alkylhydroxamate moiety. To circumvent this liability, NMR-based screening was implemented to identify alternative zinc-chelating groups. Using this technique, 1-naphthyl hydroxamate was found to bind tightly to the protein (K(D) = 50 microM) and was identified as a candidate for incorporation into the lead series. On the basis of NMR-derived structural information, the naphthyl hydroxamate and biaryl fragments were linked together to yield inhibitors of this enzyme that exhibited improved bioavailability. These studies demonstrate that the NMR-based screening of fragments can be effectively applied to improve the physicochemical or pharmacokinetic profile of lead compounds.
authors.affiliation: Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Hajduk
authors.forename: Suzanne B
authors.initials: SB
authors.lastname: Shuker
authors.forename: David G
authors.initials: DG
authors.lastname: Nettesheim
authors.forename: Richard
authors.initials: R
authors.lastname: Craig
authors.forename: David J
authors.initials: DJ
authors.lastname: Augeri
authors.forename: David
authors.initials: D
authors.lastname: Betebenner
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Albert
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.forename: Robert P
authors.initials: RP
authors.lastname: Meadows
authors.forename: Lianhong
authors.initials: L
authors.lastname: Xu
authors.forename: Michael
authors.initials: M
authors.lastname: Michaelides
authors.forename: Steven K
authors.initials: SK
authors.lastname: Davidsen
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Fesik
mesh_terms: D000818:Animals; D001682:Biological Availability; D020134:Catalytic Domain; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D019278:Matrix Metalloproteinase 3 / Q000737:chemistry; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D009281:Naphthalenes; D011480:Protease Inhibitors; D019278:Matrix Metalloproteinase 3