title: Design, synthesis, and biological evaluation of matrix metalloproteinase inhibitors derived from a modified proline scaffold.
abstract: The synthesis and structure-activity relationship (SAR) studies of a series of proline-based matrix metalloproteinase inhibitors are described. The data reveal a remarkable potency enhancement in those compounds that contain an sp(2) center at the C-4 carbon of the ring relative to similar, saturated compounds. This effect was noted in compounds that contained a functionalized oxime moiety or an exomethylene at C-4, and the potencies were typically <10 nM for MMP-3 and <100 nM for MMP-1. Comparisons were then made against compounds with similar functionality where the C-4 carbon was reduced to sp(3) hybridization and the effect was typically an order of magnitude loss in potency. A comparison of compounds 14 and 34 exemplifies this observation. An X-ray structure was obtained for a stromelysin-inhibitor complex which provided insights into the SAR and selectivity trends observed within the series. In vitro intestinal permeability data for many compounds was also accumulated.
authors.affiliation: Department of Chemistry, University of Florida, Gainesville, Florida 32611, USA.
authors.forename: M
authors.initials: M
authors.lastname: Cheng
authors.forename: B
authors.initials: B
authors.lastname: De
authors.forename: N G
authors.initials: NG
authors.lastname: Almstead
authors.forename: S
authors.initials: S
authors.lastname: Pikul
authors.forename: M E
authors.initials: ME
authors.lastname: Dowty
authors.forename: C R
authors.initials: CR
authors.lastname: Dietsch
authors.forename: C M
authors.initials: CM
authors.lastname: Dunaway
authors.forename: F
authors.initials: F
authors.lastname: Gu
authors.forename: L C
authors.initials: LC
authors.lastname: Hsieh
authors.forename: M J
authors.initials: MJ
authors.lastname: Janusz
authors.forename: Y O
authors.initials: YO
authors.lastname: Taiwo
authors.forename: M G
authors.initials: MG
authors.lastname: Natchus
authors.forename: T
authors.initials: T
authors.lastname: Hudlicky
authors.forename: M
authors.initials: M
authors.lastname: Mandel
mesh_terms: D000818:Animals; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D061965:Matrix Metalloproteinase Inhibitors; D015394:Molecular Structure; D011392:Proline / Q000737:chemistry*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D011392:Proline