title: Inhibition of stromelysin-1 (MMP-3) by P1'-biphenylylethyl carboxyalkyl dipeptides.
abstract: Carboxyalkyl peptides containing a biphenylylethyl group at the P1' position were found to be potent inhibitors of stromelysin-1 (MMP-3) and gelatinase A (MMP-2), in the range of 10-50 nM, but poor inhibitors of collagenase (MMP-1). Combination of a biphenylylethyl moiety at P1', a tert-butyl group at P2', and a methyl group at P3' produced orally bioavailable inhibitors as measured by an in vivo model of MMP-3 degradation of radiolabeled transferrin in the mouse pleural cavity. The X-ray structure of a complex of a P1-biphenyl inhibitor and the catalytic domain of MMP-3 is described. Inhibitors that contained halogenated biphenylylethyl residues at P1' proved to be superior in terms of enzyme potency and oral activity with 2(R)-[2-(4'-fluoro-4-biphenylyl)ethyl]-4(S)-n-butyl-1,5-pentane dioic acid 1-(alpha(S)-tert-butylglycine methylamide) amide (L-758,354, 26) having a Ki of 10 nM against MMP-3 and an ED50 of 11 mg/kg po in the mouse pleural cavity assay. This compound was evaluated in acute (MMP-3 and IL-1 beta injection in the rabbit) and chronic (rat adjuvant-induced arthritis and mouse collagen-induced arthritis) models of cartilage destruction but showed activity only in the MMP-3 injection model (ED50 = 6 mg/kg iv).
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065-0900, USA.
authors.forename: C K
authors.initials: CK
authors.lastname: Esser
authors.forename: R L
authors.initials: RL
authors.lastname: Bugianesi
authors.forename: C G
authors.initials: CG
authors.lastname: Caldwell
authors.forename: K T
authors.initials: KT
authors.lastname: Chapman
authors.forename: P L
authors.initials: PL
authors.lastname: Durette
authors.forename: N N
authors.initials: NN
authors.lastname: Girotra
authors.forename: I E
authors.initials: IE
authors.lastname: Kopka
authors.forename: T J
authors.initials: TJ
authors.lastname: Lanza
authors.forename: D A
authors.initials: DA
authors.lastname: Levorse
authors.forename: M
authors.initials: M
authors.lastname: MacCoss
authors.forename: K A
authors.initials: KA
authors.lastname: Owens
authors.forename: M M
authors.initials: MM
authors.lastname: Ponpipom
authors.forename: J P
authors.initials: JP
authors.lastname: Simeone
authors.forename: R K
authors.initials: RK
authors.lastname: Harrison
authors.forename: L
authors.initials: L
authors.lastname: Niedzwiecki
authors.forename: J W
authors.initials: JW
authors.lastname: Becker
authors.forename: A I
authors.initials: AI
authors.lastname: Marcy
authors.forename: M G
authors.initials: MG
authors.lastname: Axel
authors.forename: A J
authors.initials: AJ
authors.lastname: Christen
authors.forename: J
authors.initials: J
authors.lastname: McDonnell
authors.forename: V L
authors.initials: VL
authors.lastname: Moore
authors.forename: J M
authors.initials: JM
authors.lastname: Olszewski
authors.forename: C
authors.initials: C
authors.lastname: Saphos
authors.forename: D M
authors.initials: DM
authors.lastname: Visco
authors.forename: W K
authors.initials: WK
authors.lastname: Hagmann
mesh_terms: D000818:Animals; D001168:Arthritis / Q000188:drug therapy; D001665:Binding Sites; D002356:Cartilage / Q000187:drug effects; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004195:Disease Models, Animal; D018093:Gelatinases / Q000037:antagonists & inhibitors; D007375:Interleukin-1 / Q000008:administration & dosage / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D020781:Matrix Metalloproteinase 1; D020778:Matrix Metalloproteinase 2; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014168:Transferrin / Q000378:metabolism; D015032:Zinc / Q000737:chemistry / Q000378:metabolism
chemical_list: D004151:Dipeptides; D007375:Interleukin-1; C105326:L 758354; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D014168:Transferrin; C085083:N-(1-carboxyethyl)-alpha-(2-phenylethyl)glycyl-leucine, N-phenylamide; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1; D015032:Zinc